Embryology - User contributions [en-gb]

Talk:2009 Group Project 4

2009-10-14T21:32:27Z

Z3254857: /* Changes made */

== Project Updates ==
--[[User:Z3283499|Antonio Lee]] 10:57, 2 October 2009 (EST) Hi everyone, I will be working with you during the Lab10 Tutorial and here is the news link and PDF of the manuscript for your group exercise. I encourage you to read the paper before the tutorial. Also, please indicate next to the questions below (using either your initials or student number) which one of the four questions you wish to address.
:'''Group 4 :''' [http://www.scientificamerican.com/article.cfm?id=stem-cells-from-fat-cells '''Induced Pluripotent Stem Cells Created from Fat Cells'''] in Scientific American Published online 8 September 2009 [[Media:ANAT2341_Lab10_2009_Group 4 Reading.pdf|Manuscript (PDF): Feeder-free derivation of induced pluripotent stem cells from adult human adipose stem cells]]

:Question 1. What is the background to the existing problem / disease condition?--[[User:Z3252340|Emily Wong]] 13:41, 8 October 2009 (EST)
:Question 2. What approach / method did the research team take to tackle / improve the problem? --[[User:Z3252231|Angama Yaquobi]] 19:27, 7 October 2009 (EST)(Angama Yaquobi)
:Question 3. What was the breakthrough / major advancement OR failure / drawback? and why might this be of significance?--[[User:Z3224449|Elide Newton]] 13:43, 8 October 2009 (EST)
:Question 4. What are the next steps in moving forward? What are the next or new hurdles to overcome?--[[User:Z3254857|Begum Sonmez]] 12:42, 8 October 2009 (EST)

==Constructive Criticism of Coordinator==
--[[User:S8600021|Mark Hill]] 08:07, 8 October 2009 (EST) The following comments are general in nature in no specific order, as it would be inappropriate to suggest specific changes and then assess the final project. Comments will be added during this week and you still have one week before final submission.

* The project has improved in content and layout from the original submission date.
* A general comment about images. When you click an image and it opens, the information below the image should have an explanation of what the image shows, a reference (if from a paper) and a link to the original source (if available) as well as copyright information.
* There are still issues related to page design with large white spaces visible.
* [[:File:Mice_expressing_GFP.jpg]] What is the original source of this image? Do you have permission to reuse?
* [[:File:Transgenicmouse.jpg]] © 2009 Nikon Instruments Inc. can you reuse?
* [[:File:Genetics of laboratory rodents.jpg]] What is this transgenic mouse expression pattern showing?
* The Theiler images of embryo stages are useful to have, are they really all redrawn? I will be comparing these to the original online versions and they cannot be direct copies without permission.
* [[:File:Mouse_theiler_stage8.JPG]] Reichard's menbrane?
* Glossary still incomplete.
* Reference could be tidied up.

==Constructive Criticism of Peers==

--[[User:Z3218657|Sally Clarke]] 09:59, 1 October 2009 (EST)Well Done!

I'm just jumping straight into it..

- I Think the timeline stage is fantastic - the images and information are displayed really well

- the staging information is a little cramped and thrown in together - it doesn't flow very well and the images are all over the shop

- The history section has A LOT of information an images of the scientists, what they did and how they did it - great... i know this would have taken a lot of work but its a bit long. I think maybe making it into a timeline on different pages might help this.

- The headings and sub headings are really good and informative but there is a few formatting errors which is easy to fix

- The genetics sections is really good, nice and concise yet informative

Great assignment guys!

--[[User:Z3258567|Sando Rashed]] 09:12, 1 October 2009 (EST)hey wow lots of information in this page :D, well done with the effort use all put in it looks and sounds goood, few things im not sure if it was my computer but staging of embryonic development there was just a bunch of photos and they were crammed up and overlapping each other making it very hard to read use might want to cut down on the photos in that area or scale them down to make it easier to read. you have a lot of information in your history section its good that you have what they do and their contribution to make it look a bit better you might want to split it up into a 3 way table (name/what they do/how it helped) minimise the reading as i recall dr mark saying to much reading is not something he wants he wants something more appealing to him where he can lay in bed and mark it without falling asleep so a table would be good here. other than that its a great page :D well done hope use all do well!!

--[[User:Z3223194|Bronwyn Lewis-Jones]] 08:53, 1 October 2009 (EST) Congratulations on a great assignment. There are so many good things about this page. I think the biggest (and easiest) improvement to be made is to cut down on the amount of headings for the History and Current Research. The headings used such as "What did they do?" etc are helpful in showing the reader what exactly they are to understand from what is written, however they interrupt the flow and spread out the information so that it seems rather daunting. If you can summarise each section into a few sentences then I think that will not only reduce your contents section to a more useful size but also make the page more reader friendly. If you don't like that idea you could strike a happy medium by either having you "What did they do..." to bold instead of a heading or have (in bold or italics) a very short summary sentence under the name followed by a short few sentences. This would still give the reader an impression of what do get out of each section but would increase the flow inside and between notable researchers etc. Hope you find this helpful. :)

--[[User:Z3218146|Julianna Lam]] 01:31, 1 October 2009 (EST)
- the history section is TOO long ! the structure of the history section is good, i liked the whole idea of the sub headings ie ' what did he do?' but i think you guys included way too many people in there. the layout of the history section is not very neat and very inconsistent. you provided pictures of some people but didnt provide pictures of others. there are gaps everywhere and it just looks really messy.

- the stages and timeline parts are really good. the table looks really nice. and i especially like the pictures, very well labelled.

--[[User:Z3186093|Jenny Guy]] 18:46, 30 September 2009 (EST)

Improvements:
* The history is wayyyy too long. Seriously, there are too many sub sub sub headings. Cut it down and for each scientist make it a paragraph instead of so many dot points. I almost couldnt be bothered reading them all. Definitely not a good way to represent information. Looks as though you gave up on looking for pictures of the scientists. I would too if i had that many of them. Pick the main scientists that caused a breakthrough instead of listing all 1000 of them. Also, it is inconsistent if you did decide to keep the subsubsubsub headings as 'what he did', "what he found" and "what the importance" are generally all targeting the same question.
* I think you guys are confused as your information is conflicting. Humans have 23 pairs of chromosomes. In your introduction you state they humans and mice have the same number. However in the genetics it states that mice have 20pairs. What is true?
* There are a few gaps (large random spaces) in the genetics sections. Might want to format this a little.
* For the current research see the same massive point i mentioned first....
* Your referencing in the bibliography is inconsistent. Stick with one type of system, e.g. apa OR harvard. Some of the references aren't even referenced properly. You must reference websites.
* You haven't referenced ANY of you text. How do we know you havent just cut and paste? You need to either reference within the text (e.g. Andrews, E.A. (1895) states .....) or at the end of sentences/paragraphs with (Andrews 1895) or the number used in the bibliography.

--[[User:Z3255007|Sadaf Masood]] 15:43, 30 September 2009 (EST)Hey Group 4! Congrats on your great project guys! I have listed few points that might help:

1. Very well researched History section, lots of people doin lots of work..maybe you can make it a little short as its just a little too much info on them.

2. A bit more proper formatting, lots of gaps after every picture and table, maybe you can get rid of them

3. Timeline is great, just enough info to make sense and needed.

4. 'Why use of mouse is important?' this issue is well discussed. Great work!

5. Impressive hand drawn diagrams, any chances of making them a little larger on the main page? it would look really good!

6. Glossary is also needed...will make our life easier is understanding few words.

Rest is all well guys. The current research Section is awesome, very informative and lots of details. Its a great project guys...Best of Luck!!

--[[User:Z3218792|Gabriela Pinget]] 12:59, 30 September 2009 (EST) Hello! constructive criticism as follows:

- intro is a nice ease in but needs to be edited for grammar

- wow the history section is very well researched. I like that you've included so many contributors but are you sure you need to go into so much detail? It looks a little cluttered and detracts from the overall purpose of the assignment. Think about cutting down on it a little

- I really like the ''staging of embryonic development'' section! very engaging and well formatted! well done

-I also liked the timeline of development. I like that there was not too much information at each stage, but just enough to give a clear outline. Maybe a link to find out more would be useful

- genetics section is perfect

- again, the current research section is a little too spread out. The continuous "what did they do..." works well to begin with but after a while gets to be too much

Overall, a really nice looking page

--[[User:Z3295026|Joe Nassif]] 17:59, 29 September 2009 (EST)

Awesome looking wiki page, mouse group 4 an excellent assignment.

It is a really interesting reading and viewing your wiki page the content flow really well when reviewed.

1. The assignment is impressive it outlines the point with the use of sub headings which is always useful in the project as a referencing point.

2. (What did he do?) and (What did they find?) is a great way to state the history as it allows the reader to quickly get the brief information and understand it , also the illustrations throughout the assessment was great it referred to the text really well, which supported the info impressively. The hand drawn images in the (staging) and (timeline) sections were extremely great the detail was impressive.

3. Some ways to improve the assignment:
A) There are some unnecessary data throughout the project which are not relevant for example the ‘length of mouse embryo’ , removing this sections can truncate the assignment which would enhance the structure.

B) Current research information on the background of the research finders reveal great info on the development of the model usage, the findings and the relevance to human embryology have been summarized greatly.

C) The referencing need to be fixed in proper format. Visit : www.lc.unsw.edu.au/onlib/ref_apa.html for help with APA referencing

D) a glossary is needed to help the reader understand terms.

Overall a great project. The criteria was covered really well it, stated specfic topic in regards to the mouse and it embryonic developent which group 4 has summarised really well.

--[[User:Z3295026|Joe Nassif]] 17:59, 29 September 2009 (EST)

--[[User:Z3217015|Mitchell Mathieson]] 09:39, 25 September 2009 (EST)Page looks good. I liked how there was heaps of information on the genetics and the current research (however, this was a bit too spread out maybe). There seems to be a lot of gaps in the text, so the formatting could be maybe tightened up. The references maybe should be formatted better, and there is repeated information (tables and text for stages), but I really like how clicking the image goes to another page with more information...that is cool. The drawings are cute as well. Overall very good, I think formatting was the downfall from that, but the information is top notch.

--[[User:Z3126328|Jin Lee]] 16:42, 26 September 2009 (EST) hellow group4~ very impressive assignment guys!well done! I really enjoyed reading your assignment. it was easy to read and the information was relevant. However, I found the formatting of the images and texts were too sqeezy. may be resize the images and line up with the relevant information. Also, I think the reference needs to be looked after as well. Overall, the contents of the assignment is very useful and interesting.

--[[User:Z3187802|Vishnnu Shanmugam]] 20:02, 26 September 2009 (EST)Congratulations mouse group on an excellent assignment. It is a real joy to read. One of the best features of the assignment is how it gets straight to the point with the use of sub headings “What did he do?” & “What did they find?”. Even the images used throughout the text are interesting, especially the fully labeled hand drawn images in the “staging” and “timeline” sections. Some ways to improve the assignment:

-There are some unnecessary graphs in the assignment such as “the average length of mouse embryo”, “number of cells” and “number of somites”. These could perhaps be combined into a single graph. It will also reduce the congested appearance of the assignment as it seems too densely packed with no particular focus.

- In current research section, it is advisable to reduce the number of research and focus on just a few but provide more comprehensive information on the background of the research, the findings and the relevance to human embryology. It currently contains too many different types of research that have described very briefly.

- Edit the "content" section at the top of the page as it's length seems to be getting out of control. It is perhaps better to exclude the sub headings “What did he do?” & “What did they find?” in the contents.

- The referencing in the text need to be completed as there are some sections well referenced and others with no referencing. see www.lc.unsw.edu.au/onlib/ref_apa.html for help with APA referencing

- A Glossary would also complement the text.

Overall a classy project, only some changes necessary

--[[User:Z3126345|Gang Liu]] 16:49, 27 September 2009 (EST)This is one of the better wikipage i have seen so far. It demonstrates not only extended literature research skill, but also an in-depth understanding of the topic. The content of this page has been consistent throughout. In addition, paragraphs are straigtforward and concise, and make the point. Detailed texts with accessory graphics are appropriate in here. In paticular, history section. It describes the model use in terms of details of experiment, and results of experiment. Stages and timeline are very self-explanatory and visually enhanced.

This project can be improved by considering the following points.

*Lack of glossary list. Need to provide meaning of words such as "polyestrous", "oocyte", "Ectoderm", "endoderm", etc;

*Reformat stages section. I found this section a bit "busy". Might considering resize the pictures.

Last few words. I have learnt from this page that mouse has the same size genome as the human genome; Mouse genes can be easily manipulated and studied; Mouse a high degree of homogeny with humans. Well done!

--[[User:Z3217686|Thomas Dangerfield]] 14:12, 28 September 2009 (EST)Hey guys! Wow so much info first off! Not entirely sure we need to know about everyone involved in the history, maybe could have collaborated and joined people together or possibly even left certain people out. To me, the whole page is like how mark described, with everything all one great smudge of info with no real formatting or sequence or continuation. It was just kind of like an overload and reading it was a little difficult at some stages. Also corresponding the images in the timeline could have been included in the text.

Also I think your numbering of figures is a little off in the timeline section, with figures 1-4 on the right and then you have figures 4-7 describing stages 12-14. Just seems that there is two figure 4's for two different images.

Love the large amount of research and information, but could just work on your presentation and you'll do fine! Great work guys!

--[[User:Z3185685|Sumaiya Rahman]] 16:56, 28 September 2009 (EST) Hey guys! Overall a very nice assignment with a great deal of information! You can tell you guys did a lot of research. The contents are massive! Maybe you could cut this down and not use so many subheadings such as “what did they do?”, “what did they find?” and only have a subheading for each researcher. The introduction is well written. The history of model use has some really good information. My only criticism in this section is that there are a lot of gaps and blank spaces. You just need to delete all the spaces. The staging section showed a lot of research and effort. Well done!! The only thing is, is it a bit too much? There are a lot of tables and images that it was hard to keep track. Maybe this could be set out differently and made to look less busy. The timeline of development is fantastic and set out really well. It is very easy to understand and the drawings are great! Once again the current research is very spread out with lots of spaces. Also adding a glossary may help the readers in understanding the text. GREAT JOB!

--[[User:Z3215682|Carly Mooney]] 11:49, 29 September 2009 (EST)
I think all your material is there but the page layout needs work. Especially the history of the models use.
*The spacing and images are inconsistent. I liked the history of timeline section information and how it was presented, just the spacing of it all needs to be even.
*The stages of embryonic development was a little all over the place, and very daunting to look at.
*A glossary would help.
I think you guys did a really good job and just have to work on presentation.

--[[User:Z3220040|Joanne Raffel]] 16:14, 29 September 2009 (EST) Very impressive page, however it was very long!!! The introduction was very clear and concise. The history section was extremely long and poorly formatted, there were too many pictures with too little information, I would recommend cutting some of the images and just keeping the pictures of those who made a significant impact upon the mouse embryo, I also thought it was unneccessary to write after each subheading, what did he do and their result, I would prefer if it was just one paragraph. Your main heading were overshadowed by the subheadings and the rest of the text. There is a lot of information for the staging section, which is good however it can made it difficult to read, I would recommend having some of the information linked onto a separate page. The picture and format for the timeline section was exceptional however it lacked information, I also thought that it was irrelevent rewriting the timeline after the pictures, I would recommend including it with the picture rather than after it and the graph size made it seem insignificant. The genetics section was very extensive and I thought some of the information was better included with the current research. Similar to the history section, I thought the formatting of the current research section was very unorganised and too spaced out. Overall a very nice page.

----

--[[User:S8600021|Mark Hill]] 01:46, 8 September 2009 (EST) Well the content is there now, but what a mess, and I am not just talking about the formatting problem which can be easily fixed, you have no structure to your project, its not a matter of throwing everything at a wall and seeing what sticks. Work together for an integrated coverage. Timeline of development, is not the way to start your page with a huge table of data.

--[[User:S8600021|Mark Hill]] 08:43, 21 August 2009 (EST) OK guys, time to see some actual content uploaded on both your discussion and project pages.

* Timeline of Development - how long (Emily)
* Staging - are there species specific staging, what occurs when (Elide)
* History of Model Use - when was it first used, what embryology research (Begum)
* Genetics - chromosome number, sequencing (Angama)
* Current Embryology Research - research papers and findings (All)

Here is a link for timeline
[http://books.google.com.au/books?id=XLIarRWHikAC&pg=PT199&lpg=PT199&dq=mouse+embryo+development+timeline&source=bl&ots=fobLBRiacx&sig=cK4cuZah6Ksczs3o8v4NXQqoAyk&hl=en&ei=rGB6SvTHMMmIkAXB_piAAw&sa=X&oi=book_result&ct=result&resnum=3#v=onepage&q=&f=false
]

link for the mouse brain development timeline http://en.wikipedia.org/wiki/Mouse_brain_development_timeline

hey guys there is another interesting link about mouse development http://mouseatlas.caltech.edu/index_content.html

Hey Emily. The link below has a timeline that you can check out in your spare time. Begum.
[http://books.google.com.au/books?id=4juoa5xMs8oC&pg=PA31&lpg=PA31&dq=mouse+embryology&source=bl&ots=9tJAfRG4R6&sig=hjR5Zs-sL1sCW5FY8FnR5TMaUk0&hl=en&ei=LuuMSr_aCNjakAX714icDA&sa=X&oi=book_result&ct=result&resnum=9#v=onepage&q=mouse%20embryology&f=false]

Hi girls,
here is a link to a text book about mouse embryology it looks pretty good. hope it can help
[http://books.google.com.au/books?id=4juoa5xMs8oC&printsec=frontcover&dq=mouse+development&source=gbs_similarbooks_r&cad=2#v=onepage&q=mouse%20development&f=false]
let me know if the link doesnt work. Ive been working on the main page, so have a look and tell me what you think, Also what are we doing about references? If we have used information but put it in our own words do we need to put in text citations,or do we just reference the journal at the end? I just want to be very careful. Thanks!

Hey Elide, i think your work is looking really good. its very easy to read and understand. keep going!!!! emily

hey everyone,
I have uploaded some of my timeline work. I'm not sure if I've gone into to much detail or not and also on how is best to present the timeline. It is fairly basic and definately needs some work - especially on presentation, grammar, etc. let me know what you think.
Emily

good site for stages or timeline- atlas of pictures of stages- The Edinburgh Mouse Atlas Project [http://genex.hgu.mrc.ac.uk/]

Hello girls, it's Begum. I put some info under the history section. Wanted to let you all know that I've got a fair bit of info, and I will do my part as best as I can. Btw Emily, I think maybe dot from would be best for you, but if you can use those lines that I was talking to you about on Wednesday, that would be great...I know it's hard.

hey everyone, i have put some info under the genetics heading and some under research. I am still struggling to find the appropriate info related to the topic of genetics because there is alot of info abt the different types of stains used in labarotories but not the genetics. I emailed Dr.Hill and have asked him what to include in my section specifically,hopefully he will help. So far i have just started it needs alot of more work to be done,girls just read thru my section n leme know wt u think of it. have a nice weekend everyone. Angama.

Hi girls!
Begum, you history info is really good. If very interesting! I really like how you are doing it in order of dates of discovery and what they did, what they found etc! Cant wait to know more.
Angama, your doing well! it sounds like your finding the info hard to get. I'll keep an eye out for you! If your stuck on what you sound be doing then i might have a few ideas. I remember Mark Hill saying that you should compare the genome to the humans genome. so maybe if the genome is the same size as the humans, could you descibe similarities or differences? I know that there is a link to the mouse genome on the mouse web page he gave us ( next to the discussion link). Are you just ment to list the mouse genome sequence? could you go into what genes code what, eg which one codes for the sex linked gene, is it the X and Y gene etc? hopefully Mark gives you some ideas.
well as you might have noticed i've been adding to my stages. the only thing is im worried about there being too much info up there. basically ive tried to get all the info available included in my stages to make sure i cover everything, and then later i'll go over it all and edit and polish it up a bit. Ive done some drawings to the best of my ability, but i can scrap them if you all think they arnt professional enough. just thought i'd try to present the information differently. let me know if you think i'm including too much information. i think i'm having the same problem as you begum, there is lots of info! Elide

Thanks Elide. I'm trying. (Again, loved the artwork!)Btw, Emily, I had a think about your section and I think it might be too much 'clicking' back-and-forth if we link the displayed pic to the 'info' page. Don't stress, you've got the info (heaps which is excellent) but make sure you get some pictures soon so we can start drawing (I'm helping with the drawings as well ok). Mark said 'Nature' and 'Science' have useable images so lets make that our start.
BTW, I will be using the question mark symbol(???) so I don't forget to reference. Begum

Hey everyone, I have found an online text book. it has a chapter on genetics and history and a lot of other stuff. [http://books.google.com.au/books?id=Vt6nUmz1yEQC&pg=RA1-PA207&dq=mouse+development+anatomy&client=firefox-a#v=onepage&q=mouse%20development%20anatomy&f=false] Emily

Hey girls. If you've seen my section, the info is not on the main page, but linked to another page. I thought that it might make everything look more neat. I thought we could all do it like that. It's just an idea. Something different. Maybe we could have something on the main page (picture of a mouse). Your thoughts everybody? Begum

hey begum, ur work looks really good. i like the idea of linking the work to another page. - we don't have to worry about to much info being on the front page and it gives people to option of viewing the work if they want to. ive been working on drawings, i'll show them to you next week but am not sure how to upload them at the moment. Emily

Thanks! That sounds great that you like the idea. About the photos that you are drawing, if there by hand, you can scan them somehow. But overall,
1. click 'Upload File' on the left hand side of this page
2. New page comes up: click 'Browse' and choose your file that you want to upload.
3. Name it (under the Browse button)
NOTE: write down what you named the file as because like Elide says "...it's going to be lost in space!..."
4. Write down info/comments (like who is the author (YOU), and if the drawing is based on a picture)
5. UPLOAD!
6. Go to your section and just normally type this down to the area you want the picture to be seen:
[[image:THE NAME THAT YOU SAVED THE FILE UNDER.jpg|thumb|200px|right|WHAT YOU WANT THE FILE NAME TO VISUALLY COME UP AS]]

Your thoughts Angama and Elide? (about the linking of our sections to separate pages?) Begum.

Oh and another thing:
What do you girls think about my page, I've got a heading for each DATE and underneath each there are further subheadings (e.g. 'What did he do?'. Should I change them to just text, I mean, does it look messy with sub-sub-headings? Begum.

wow girls! great work.. okay so i asked mark about a new page and he said to avoid it because our info is meant to be on our one page. he said if there is extra information on what we wanted to say but is too much for the main page then have a link to our discussion page. (which is what im going to do) Begum your new page is fantastic!! you have done lots of work! but why dont you just put it on our main page? also girls i think we are getting too carried away with info. just keep it simple! i'm sorry i havent been around this week to work on it but i plan to get going asap. just fixing up some things, summarising, writing introductions etc.
did you all read his note about slabbing info onto our page?? how about some introductions, and sentences to ease ourselves into the content. planning on trying to work on that now anyway..

also lets get the information flowing. why dont we go intro, history of model use, stages, timeline, genetics, then current use.. what do you all think?

hey, i thing that that sounds like a good, logical way to do the page. i've finished the drawings, just need to upload them. About the timeline information, is there anything specific that i should include. the stuff that is on the page is a little vague and so i need some advice as to what are key points that i should include. i know that the drawing are very simplistic, let me know wjat you think about them. ive put one up below. i just need a way to link it to text. emily

Thanks Elide. You know, I think that's a great idea. Have it all on one page, seems less 'diverging...', seems more COMPLETE. I love the ORDER as well. I'll fix all that up!

Hey girls, please have a look at what i've done on the timeline. the images are all hand drawn based upon the text: 'the house mouse'. if anyone could give me any ideas on how best to present the pictures - which would be better - next to or below the text? keep in mind that it is incomplete and there is an illustration for each day of development (i.e. 19 in total). if you think that is too many let me know, some may be similar to Elide's ones. Also, do you think i should put some colour into the drawings? Emily

I love your work Emily. All you need to do is put the info on the growth of the mouse that is on the main page, onto the page with the graph of the growth of the mouse embryo...we talked about that before any way-AND I think your parts finished! Begum.
Angama, I added something to the end of your section that I thought was interesting. Have a look. And are you mentioning manipulation and 'shut-down' of the genes in your section?? Begum.
To everyone, apparently ''Mus Musculus'' is the scientific name of the common house mouse, not the mouse. I was thinking of editing that.

HEY EVERYONE! well i've added in some pictures just to make it look more visual, change them if you have better ones.. and i'm going to be working on the current research section tommorow. oh i also added some graphs like we thought of for emilys section.. so i think my section is finished finally! what do you think? can i just say, I think the whole thing looks great! you girls have been a pleasure to work with! :) Thanks so much!!

hi girls, i am sorry..i have been very busy during the mid-sem break and i know we all had our exams and assignments due. but i was having some issues in my family and also the exams and assignments so didnt really had the chance to read wat u girls have got on the main page. i just finished reading thru it and it looks amazing..WELL DONE GIRLS!! you all have done a marvellous job...Eldie and Begum thanks for suggesting some main points to add for the genetics.i am currently working on it.. hopefully tonight i will have all the information on the page..Begum i love how you have presented alot of info into a very easy and understandable way..it makes so much sense..n it looks very nice with the pictures. Eldie and Emily great amount of work and the pictures and the graphs are superb. i just had a look to other groups pages. n i think so far our page looks very interesting with concise info n amazing pictures. n Begum yes i read what you have added thanks for tht..i will cu girls around..gudluck everyone. cheers. Angama.

Girls can you please help me out.. i am so annoyed..
like rite now i was typing some info and when i clicked to save.
it says "conflict" so i think some one else is also editing
the page at the same time that i am. and i lost all my work..arghh..
so which means i have to type it all again.
is there any other way that it tells me that someone else
is also using it so i dont click on save or even preview
because when i do tht i lost all the work tht i had.
If anyone knows please let me know. thanks. Angama.

Current research : I have put some information in the current research part. not sure where they should be put. Begum, as discussed you can edit it or place it in its appropriate place.

Don't stress Angama at all, now you know, it will be over soon. Uploading it easy:

1. click 'Upload File' on the left hand side of this page

2. New page comes up: click 'Browse' and choose your file that you want to upload.

3. Name it (under the Browse button) NOTE: write down what you named the file as because like Elide says "...it's going to be lost in space!..."

4. Write down info/comments (like who is the author (YOU), and if the drawing is based on a picture)

5. UPLOAD! 6. Go to your section and just normally type this down to the area you want the picture to be seen:

It's easier than it is typed! Of you still have problems I will be at the embryo lab, of there is exams there the ANAT LAB opposite to it, if not Level 3 library computers.

[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19538749| maternal diabetes alters transcriptional programs in the developing embryo], [http://www.ncbi.nlm.nih.gov/pubmed/19414407?ordinalpos=35&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum|Abnormal mammary gland development in MMTV-CBLC transgenic mouse], [http://www.ncbi.nlm.nih.gov/pubmed/19394325?ordinalpos=40&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum|Sonic hedgehog signalling inhibits palatogenesis and arrests tooth development in a mouse model of the nevoid basal cell carcinoma syndrome.], [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=55&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum| Fibroblast growth factor 18 gives growth and directional cues to airway cartilage.]

Hi girls, i think i have completed my section. could you all please just read thru it and leme know wat you think of it. i did it to the best of my ability. Hopefully you will all like it if you girls think therez anything more to add or to delete leme know..thanks. gudluck girls. Angama.

Angama your work is fantastic! Thanks so much! im sorry i wasnt around to help you with the problems. hope it went okay. your info is perfect! im very happy with our page! lets hope everyone else is :)

I love it Angama, good work! And the pictures you uploaded are very interesting. Cool. Awesome. Your done!! Begum.

Thanks Begum :) Girls gudluck and cu all tomorrow. Angama.

== Discussion after peer assessment and constructive criticism ==

Hi girls,
Ive started making some changes to the page based on the comments recieved.
Note i've also started a glossary of terms. Also many of our comments regarded our references,so It would be great if we could all reference the same, lets say APA because this is the most common way for referencing. I have gone through our references and tried to format them in APA. many are incomplete references so i have bolded the references that are missing detail. please if you all could complete your references that you added to the list. Also shall we number the references so we can include the numbers in the text as in text references? like foot note? what do you all think... there have been many comments on our current research page.. so how would you all like to fix it? I personally think its way too much. It seems to have accumulated heaps of info from when I last saw it. Is there anyway of summarising the current research info to focus more on how they are used rather than the institute and scientists involved. I think the most important info in this section is what mice are being used to discover currently and proof of the year of study. Cant wait to hear what you all think! Elide

one more thing.. ive tried to edit the contents, as one of our peers suggested, however i cant seem to edit it. do any of you know how to do this?
Elide

hey emily, i see you have reduced the heading in the contents!! thats great! i was just thinking that maybe we dont need so many headings in those 2 sections at all. what do you think about just making all the scientists and the names of people/ labs just in bold.?

Hi girls, have a look at the changes i have made to my section. let me know what you think. Emily

looks good!!
also girls could you please add words from your sections to the glossary, as that whole list is only from the staging section. thanks. elide

Hello girls. I will be re-formatting the history section in order to get rid of the 'gaps' that my peers have mentioned. Also, Elide mentioned yesterday that placing all the 'History' pictures towards the right-side of the page would look more neat, as well as add to the flow of the page. I think this is a great idea. Begum. Oh, and '''what do you guys think about taking out some information (findings)?''' Some students have mentioned that there is too much information/researchers.
And Elide, I'm might change the names of the researchers. like you said before, to bolded text. It would look much more neat. I might, also, '''apply this to the Genetics section. What do you all think?'''

'''Begum's Problem'''
Hey. I placed all pictures to the right-hand side (history section), but the pictures don't correspond well with the text. Any suggestions?? Should I than put the towards the left? Love the change to the timeline section Emily.

HEY BEGUM!!
so your problem.. I dont think the pictures need to match up because if they have a title of the person then the reader can find their picture. plus the comments are on the spaces and gaps between text, not the pictures.. so maybe just put them all underneath each other and even if they dont match up then at least the writing looks more organised. try making the images 200px and not so large and it could work better?. also the bit about taking out the headings in the genetics would be great!! bold would still look fine! goodluck! xox

--[[User:Z3254857|Begum Sonmez]] 14:54, 10 October 2009 (EST) '''TO ELIDE''': I was going to change the headings 'Reproduction' and 'Theiler Stages' under STAGES to bolded text. What do you think? Plus, like you said before, I'm on that ref. list, I will summarise the current research, and change those headings. If the HISTORY pictures match up to the the text, it would be more convenient for the viewer, don't you all think so??? However, the text would appear better the other way with the images al together on the right. Yes, I'll do that.

Hey '''Begum'''!
yes what a great idea about changing the headings in the staging section! the whole page needs to have the same structure throughout! I shall change them right now! :) i'm a little confused about the bit you said about what you said about the ref list. do you mean that you will fix yours? ive been through some of them and looked up the missing details. some are lacking their full reference though. but that would be so great if you could fix up your references. i think the ones in bold are the ones still needing work, but correct the others if you think they arent finished.
well i think the history section looks great! even though the pictures dont match up, they are still there and they look neat and have the same format as the rest of the page. and even better there are no spaces! so it looks great!! i wouldnt worry too much, you've done a such great job providing detail, the pictures are just a bonus!
the reference list looks great! thanks for your help! xox Elide

--[[User:Z3254857|Begum Sonmez]] 20:55, 11 October 2009 (EST)Hello girls! One more thing left: Current Research section. One student said to reduce the number of 'research', but include more information on each. I don't think adding more info under the research is necessary. But '''just keeping the 'breakthroughs'''' would be good, the more important ones. What do you all think? Also, '''what should the headings be''', any suggestion? Should I keep the Organisations as the headings, or the names of the researchers involoved, and/or the dates?

--[[User:Z3224449|Elide Newton]] 11:41, 12 October 2009 (EST) hey. about the current research section. well now that it doesnt have as many spaces and gaps it doesnt look as long, so maybe thats why the student saids to reduce the number of examples. so i'm with you begum, keep the important ones. for example if there are 2 examples of its use in cancer then have only one cancer example. yes headings . i think maybe keep the organisation and date. see what the other girls think.. i'll have a think about it too, and see what we can improve on that section.. overall are we all happy with how its looking? i think its looking great! even the reference list doesnt look messy! :)

--[[User:Z3224449|Elide Newton]] 14:48, 13 October 2009 (EST) Begum! your work is amazing! the current research section looks so much better! I think the page is starting to come together now! what i plan on doing is giving the whole thing a good proof read to make sure the flow, format, text, and info is consistent throughout. what else should we do with it. is everyone liking the improvments so far? dont forget we only have tomorrow to work on it!

--[[User:Z3254857|Begum Sonmez]] 19:43, 13 October 2009 (EST)
Thanks Elide!! I have and will continue proof reading the history and current research section (for any mistakes and grammar issues), so you don't need to proof read those sections in-depth (save you time). Just to let you all know, I may or may not get rid of some current research findings. I think we all did a great job, and our page looks very organised and professional. Well done to all of us.

--[[User:Z3252231|Angama Yaquobi]] 23:14, 13 October 2009 (EST) Hi Girls, as you might have noticed that I have changed some of the images in genetics section and have included more information about each of the images along the source info. I have read and viewed the History section and Current Research, it looks very nice in terms of formatting with alot of improvement, so i am really happy Begum you have done a great job, well done! Eldie I have added few images but am still not sure about one or two images if it has given permission for its use for general public. If i see you on thursday before the start of the lab i will show it to u so that you know what i mean. Like it doesnt say anything about the image that it cant be copied unlike some other websites tht at the bottom of the page it gives u a brief detail regarding the copyright policy. So may be i will tell you on thursday during the Visceral lab. :-) I have also added some terms in the glossary list and I think our page looks amazing. Lets hope that Mark like it. Everyone's section in my perspective looks very interesting and informative. So well done everyone.

--[[User:Z3224449|Elide Newton]] 17:21, 14 October 2009 (EST) '''TO ANGAMA:''' so i had a look at your images in the genetics section. i took the link to the webpage where you got them from to look for copyright laws. unfortunately i couldnt find anything on copyright for all of your images. and without copyright approval they cant be published on our page. so this isnt so good. for the 2 images 'transgenic mouse pup' and 'Conditional Gene Expression' these could possibly get approval from the author Wes Thompson by possibly emailing '''resler@mail.utexas.edu''' . The only thing is the lack of time we have left. the image of the researcher in the current research section doesnt have copyright either, so we might have to get rid of this completely, at least its only showing people and isnt vital to the understanding.

*The image 'Examples of some commonly used mouse strains' has no info describing the point of the picture or source or copyright. does anyone know info about this image, otherwise it shouldnt be on the page.
*The Image of Transgenic Mouse also doesnt have copyright approval.

We just need to fix these few things. so girls if we cant get copyright laws for the images do you all agree we need to remove the images? this is so unfortunate because they are such great images!! :(

overall i'm very happy with our page. I think we have all worked very hard on this assignment and thats all we can do. I'll go over it one more time, but i'm happy with it as it is. thanks all so much for all your effort and work put into this assignment. it has been a pleasure working with you all! please reply asap,so we can fix the images... coz its due in the morning!!!

Hey girls, the page looks much better especially now that the gaps have gone and the contents is much shorter. You've all done lots of work editing the page and it looks as though all your hard work has paid off. sorry that i have not done much editing. Based on the comments that we recieved there wasn't that much that i had to change for my timeline. --[[User:Z3252340|Emily Wong]] 18:48, 14 October 2009 (EST)

--[[User:Z3252231|Angama Yaquobi]] 23:03, 14 October 2009 (EST)
Hi girls, I have removed 2 images since it did not had any information about its copyright though i have added another one along the copyright info. I think that i do not need to add any more images for the genetics section because i think its enough and even though there are so many beautiful images out there in websites but unfortunately got no permission for use. So i think we all have worked very hard for this project and it was a pleasure and fun to work with all u girls. Gud luck girls with exams coming in 2 weeks time.

== List of things still to do ==
* proof read the whole thing
* check if your images have info underneath, reference and copyright liscence (Angama you might need to check your genetics pictures.) If your busy I can do them for you but i need to know the reference and copyright permission. Elide

== Changes made ==
--[[User:Z3224449|Elide Newton]] 12:17, 2 October 2009 (EST)
*Removed table of stages from discussion page
*Corrected introduction " the mouse has a similar genome to the human"
*In stages section changed size of images to 200px and moved to the right
*Removed spaces and gaps from stages
*Formated stages section to look neater
*Deleted the links to tables on discussion page
*Added in table of theiler stages 12-14 which was on the discussion page
*Started a glossary of terms
--[[User:Z3224449|Elide Newton]] 16:17, 5 October 2009 (EST)
*Added in text citations to the staging section
*Added in more definitions for glossary of terms and referenced glossary
*Went through each reference of reference list and changed the format it into APA, bold for incomplete references.. to note that it needs to be fixed.

--[[User:Z3252340|Emily Wong]] 11:28, 6 October 2009 (EST)
* Edited the contents so that it wasn't as long i.e. took out all the repeated "what did he do?" etcs.
* Edited current research so that contents are not as long. Again taking out the "what did the do" etcs.
--[[User:Z3252340|Emily Wong]] 15:38, 8 October 2009 (EST)
* Edited the timeline of development section by:
** Taking out the written text and incorporated it into the captions below each drawing.
** Rearranging the work so that it was in a better position
** Linked the graph 'Average length of the mouse embryo' into the section by writing a small blurb on it.

--[[User:Z3224449|Elide Newton]] 10:44, 9 October 2009 (EST)
* Removed spaces in sections current research and genetics
* Moved images to the right and changed size to 200px in current research section
* re-uploaded theiler stage 8 image with typo fixed ( reichards to Reicherts)
* added information below images in the staging section.
* added links to source below images in staging section
* deleted 'Photo of mouse vascular development at Theiler stage 20' because I am unable to find copyright liscence
* went through each ref and chagned to APA, had to look up dates and authors for incomplete references added by other students. still some are not complete (in bold) so if you added these references could you please fix.

--[[User:Z3254857|Begum Sonmez]] 12:28, 9 October 2009 (EST)
*Changed the heading 'Chromosome number and banding patterns' under Genetics, from being a main heading to a sub-heading. This was a small mistake that had to be fixed.
*Changed the sub-headings of the history section, that list the years, to bolded text. The reason for this change is that it condensed the amount of headings in the 'Contents', allowing the viewer to have an outline of the page instead of a massive list of each heading. As a result, the page looks more neat, and each section is consistent with eachother.
*Placed all pictures in the History section to the right-side of the page. This is more consistent with the rest of the page, and adds to the flow of the page.
*Placed 2 spaces between each finding, and 1 space between each part of the finding (For example, 'What did they find', 'The Importance'). Again, this is another feature which adds to the consistancy of the page. Many of our peers pointed out that our page was messy. This change helps to solve the problem.

--[[User:Z3224449|Elide Newton]] 20:38, 9 October 2009 (EST)
*Removed headings from current research section and made them bold.
*Finished the glossary of terms from the staging section
*worked on current research. (removed spaces, formated, removed lists of names and added 'et al')

--[[User:Z3254857|Begum Sonmez]] 14:45, 10 October 2009 (EST)
*Changed the sub-headings under the Genetics section to bolded text. There were no complaints about this from our peers. However, since this was applied to the History section, applying it to the Genetics section would be consistent and more neat.
*Placed all HISTORY pictures beneath one another in order to be consistent with the arrangement of other pictures throughout the page.
*Deleted some of the headings (what did they, how did they...) under the history section, as the contents of some of the headings were related. One student mentioned this. As a result, there is less headings, and a greater degree of clarity.
*Edited the Reference list by dividing it into 2 headings ('Books and Articles' and 'Webpage'), and converted some more references into APA style. Just one more conversion left.
*Added the definitions of 'Allophenic', 'Chimera', 'Corpus luteum', 'Somatic tissue' and 'Stem Cell' to the Glossary List.

--[[User:Z3224449|Elide Newton]] 19:44, 10 October 2009 (EST)
*Removed headings from staging section and made bold instead to be the same as the whole page
*Removed two gaps from the genetics section

--[[User:Z3254857|Begum Sonmez]] 14:24, 12 October 2009 (EST)
*Changed some of the Sub-headings under the Current Research section to make it more consistent throughout this section.
*Converted the information under each finding under the Current Research section into numerous small paragraphs because one student outlined that the use of the sub-sub-headings were good at first, but it than became overwhelming. This change enhanced the layout without using the sub-sub-headings and without ending up with a slab of text.

--[[User:Z3254857|Begum Sonmez]] 11:18, 13 October 2009 (EST)
*Changes the heading 'THE MOUSE' from all upper-case to lower-case. This is consistent with the other main headings.

--[[User:Z3252231|Angama Yaquobi]] 19:35, 13 October 2009 (EST)
*Removed some of the images in the genetics section because there was not much information about the image.
*Replaced those images with new images containing information about the image.
*Added the definition of 'Haploid', 'Mutation', 'Oncogenic', 'Renaturation', 'Telocentric', 'Transgenic', and 'Transposition'.

--[[User:Z3254857|Begum Sonmez]] 20:20, 13 October 2009 (EST)
*Changed the word 'Are' to 'Is' under the introduction. Just a slight grammatical mistake.
*Added to the comment under the Gregor Mendel picture under the history section, the words 'Copyright has expired'. This informs the reader/viewer about the copyright information. Proof read the Current Research section. Changed a few grammatical mistakes, and deleted unnecessary sentences. This shortened the content of each finding, providing a summary of the key points for the audience.
*Added the reference of images used under the History and Current research section into the reference list. I think this was not done by mistake.

--[[User:Z3224449|Elide Newton]] 21:10, 13 October 2009 (EST)
* proof read. added in 2 sentences to make the transition from 'history of use' and 'stages' flow.
* added a sentence in after the genetics heading to keep the flow on from the last section.
* added in Mb to The haploid genome is about 3 billion '''Mb''' long.
* changed 'tha' the 'the' in genetics section.

--[[User:Z3224449|Elide Newton]] 17:57, 14 October 2009 (EST)
* in looking for images for the genetics section which had copyright laws I noticed the 1st paragraph of the genetics section was the exact copy from wikipedia, so i rephrased the information so it isnt plagarised

--[[User:Z3252340|Emily Wong]] 19:05, 14 October 2009 (EST)
* Resized the images in the timeline gallery so that they were 175px instead of 100px. This made the images have more of a presence on the page.
* Checked spelling and grammar
* linked the timeline section with the staging section by mentioning how long the stages took.
* Put day numbers in bold so that the stand out from the text

--[[User:Z3252231|Angama Yaquobi]] 22:54, 14 October 2009 (EST)
* Proof read the genetics section.
* Removed 2 images because they did not had any copyright information.
* Added a new image "Knockout Mouse". Added information about the image and also have added the copyright information.

--[[User:Z3254857|Begum Sonmez]] 08:22, 15 October 2009 (EST)
*Removed the pictures of 'Whesley Whitten', 'Anne McLaren', 'Beatrice Mintz', 'Teruhiko', and 'Leroy Stevens' under the History section, as well as 'NIDCR' under Current Research due to unavailability of Copyright information.
*Replaced the pictures with links to the websites containing those pictures.

2009 Group Project 4

2009-10-14T21:31:56Z

Z3254857: /* History of the use of the Mouse Embryo Model */

== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Is a small organism which can be easily maintained
*Is not expensive
----

===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

Link to photo of Whesley Whitten: [http://www.mun.ca/marcomm/gazette/2000-2001/june14/convocation8.html]

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

Link to photo of Anne McLaren: [http://www.geneall.net/U/per_page.php?id=557208]

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

Link to photo of Beatrice Mintz: [http://images.google.com.au/imgres?imgurl=http://www.clas.uiowa.edu/_includes/images/alumni/beatrice.jpg&imgrefurl=http://www.clas.uiowa.edu/alumni/programs/fellows/2002/&usg=__ZTVwhRDWmWlpQWiTgm7QPANk0ow=&h=218&w=182&sz=10&hl=en&start=2&sig2=WxT11tEDMuSTsbeT1PzXjQ&um=1&tbnid=7WxPUu34U_wdOM:&tbnh=107&tbnw=89&prev=/images%3Fq%3Dbeatrice%2Bmintz%26hl%3Den%26sa%3DN%26um%3D1&ei=ECy2Sp_JKMiGkAX9k9XBCw]

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

Link to photo of Teruhiko Wakayama: [http://www.cdb.riken.go.jp/jp/03_activities/symposia/2004/profile_wakayama_e.html]

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Link to photo of Leroy Stevens: [http://images.google.com.au/imgres?imgurl=http://web.me.com/dtrapp/people2.f/EvansMartin.jpg&imgrefurl=http://web.me.com/dtrapp/eChem.f/labB6.html&usg=__piFK4fxjodtmgHG3gYq2ohJHgBQ=&h=200&w=200&sz=7&hl=en&start=4&sig2=Po8C2fKqsfDfS9vXQO6oXw&um=1&tbnid=jaSbrsNd-O4suM:&tbnh=104&tbnw=104&prev=/images%3Fq%3Dleroy%2Bstevens%26hl%3Den%26rlz%3D1C1CHMB_en-GBAU344AU344%26sa%3DG%26um%3D1&ei=tCO2SrjgJtOHkQXE0aHdCw]

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

The mouse model has been used significantly in past scientific experiments. The mouse has many beneficial qualities which allow it to be easily manipulate and studied. One example includes its ability to reproduce and embryological development.

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Fingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development, so far, a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development click the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm. The 26 Theiler stages are covered within 18 days, while stages 27 and 28 are covered during day 19 and the days after birth.
{{Insert timeline}}
----

===Genetics===
[[image:800px-Knockout_Mice5006-300.jpg|thumb|300px|right|Knockout Mice]]
The mouse is extensively used in experimental models because of its genome and its ability to be manipulated and studied.

'''Genome'''

In late 2002 the sequencing of the mouse genome was completed. Scientists have discovered that the haploid genome for the mouse is about 3 billion bases long having a total of 3000 Mb distributed over 20 chromosomes. The size of the mouse genome is closely related to the human genome size. Scientists estimate the gene count of the mouse genome to be 23,786 genes when compared to humans having 23,686 genes, a degree of size similarity can be shown.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino.
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).
[[image:Nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome. Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.

Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function. However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.

[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve in mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues [http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm] created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:

1.Supports the multiplication of the H9 cells better than the 3T3 line.

2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1/ An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155), and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on normal hematopoietic stem cells (HSCs).

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy remains uncertain until clinical trials are undertaken in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia et al. used the knockout mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knockout mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cellular differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please click [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| here] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. found that the epithelial-mesenchymal interactions in the development of the Wolffian duct and testis cord are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins, when mutated, become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin ,rather than the bacterial cell numbers, is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents, BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab, on the mice containing EGFR mutated lung tumors. It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''', which has been studied to assist in generating antibody and CD4 T helper cell responses. This process was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Haploid:''' A set of chromosomes containing only one member of each chromosome pair. The sperm and egg are haploid.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Mutation:''' is a randomly derived change to the nucleotide sequence of the genetic material of an organism.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Oncogenic:''' An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Renaturation:''' The process by which proteins or complementary strands of nucleic acids reform their native conformations.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Telocentric:''' a chromosome like a straight rod with the centromere in terminal position.

'''Transgenic:'''A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered using genetic engineering techniques.

'''Transposition:''' is a kind of mutation in which a chromosomal segment is transfered to a new position on the same or another chromosome.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Shiro, I., Meytha, M., Cristina, V., Karen, E., Walid, K., Howard, G. (2006). An immortalized drug-resistant cell line established from 12-13-day mouse embryos for the propagation of human embryonic stem cells. ''Differentiation''. Accessed from http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KJLDc4JX2vKFKSQbLw7SSJTx2pGy4dMvGQJ9zpGxDdZ5hN1YyC6H!-2135654213!181195629!8091!-1

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*Geneall. ''Dame Anne Laura Dorinthea McLaren'', retrieved September 21, 2009. http://www.geneall.net/U/per_page.php?id=557208

*Harvard University. ''Howard Green, M.D.'', retrieved September 24, 2009. http://cellbio.med.harvard.edu/faculty/green/index.html

*Institute of Medical Biology. ''Davor Solter'', retrieved October 12, 2009. http://www.imb.a-star.edu.sg/Default.aspx?tabid=224

*International Knockout Mouse Consortium. ''About the International Knockout Mouse Consortium'', retrieved September 19, 2009.

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Memorial University. ''Oration honouring Wesley Whitten'', retrieved September 11, 2009. http://www.mun.ca/marcomm/gazette/2000-2001/june14/convocation8.html

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*National Institute of Health Record. ''NIDCR Team Creates Mouse Model of Disease'', retrieved September 19, 2009. http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*University of Iowa : College of Liberal Arts and Sciences. ''Alumni Fellows'', retrieved September 26, 2009. http://images.google.com.au/imgres?imgurl=http://www.clas.uiowa.edu/_includes/images/alumni/beatrice.jpg&imgrefurl=http://www.clas.uiowa.edu/alumni/programs/fellows/2002/&usg=__ZTVwhRDWmWlpQWiTgm7QPANk0ow=&h=218&w=182&sz=10&hl=en&start=2&sig2=WxT11tEDMuSTsbeT1PzXjQ&um=1&tbnid=7WxPUu34U_wdOM:&tbnh=107&tbnw=89&prev=/images%3Fq%3Dbeatrice%2Bmintz%26hl%3Den%26sa%3DN%26um%3D1&ei=ECy2Sp_JKMiGkAX9k9XBCw

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

*Wikipedia. ''Gregor Mendel'', retrieved September 20, 2009. http://en.wikipedia.org/wiki/File:Gregor_Mendel.png

*Wikipedia. ''Rudolf Jaenisch'', retrieved September 17, 2009. http://en.wikipedia.org/wiki/File:Jaenisch_2003_by_Sam_Ogden.jpg

{{Template:Projects09}}
[[Category:Mouse]]

2009 Group Project 4

2009-10-14T21:31:28Z

Z3254857: /* History of the use of the Mouse Embryo Model */

== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Is a small organism which can be easily maintained
*Is not expensive
----

===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

Link to photo of Whesley Whitten: [http://www.mun.ca/marcomm/gazette/2000-2001/june14/convocation8.html]

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

Link to photo of Anne McLaren: [http://www.geneall.net/U/per_page.php?id=557208]

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

Link to photo of Beatrice Mintz: [http://images.google.com.au/imgres?imgurl=http://www.clas.uiowa.edu/_includes/images/alumni/beatrice.jpg&imgrefurl=http://www.clas.uiowa.edu/alumni/programs/fellows/2002/&usg=__ZTVwhRDWmWlpQWiTgm7QPANk0ow=&h=218&w=182&sz=10&hl=en&start=2&sig2=WxT11tEDMuSTsbeT1PzXjQ&um=1&tbnid=7WxPUu34U_wdOM:&tbnh=107&tbnw=89&prev=/images%3Fq%3Dbeatrice%2Bmintz%26hl%3Den%26sa%3DN%26um%3D1&ei=ECy2Sp_JKMiGkAX9k9XBCw]

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

Link to photo of Teruhiko Wakayama: [http://www.cdb.riken.go.jp/jp/03_activities/symposia/2004/profile_wakayama_e.html]

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

The mouse model has been used significantly in past scientific experiments. The mouse has many beneficial qualities which allow it to be easily manipulate and studied. One example includes its ability to reproduce and embryological development.

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Fingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development, so far, a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development click the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm. The 26 Theiler stages are covered within 18 days, while stages 27 and 28 are covered during day 19 and the days after birth.
{{Insert timeline}}
----

===Genetics===
[[image:800px-Knockout_Mice5006-300.jpg|thumb|300px|right|Knockout Mice]]
The mouse is extensively used in experimental models because of its genome and its ability to be manipulated and studied.

'''Genome'''

In late 2002 the sequencing of the mouse genome was completed. Scientists have discovered that the haploid genome for the mouse is about 3 billion bases long having a total of 3000 Mb distributed over 20 chromosomes. The size of the mouse genome is closely related to the human genome size. Scientists estimate the gene count of the mouse genome to be 23,786 genes when compared to humans having 23,686 genes, a degree of size similarity can be shown.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino.
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).
[[image:Nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome. Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.

Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function. However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.

[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve in mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues [http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm] created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:

1.Supports the multiplication of the H9 cells better than the 3T3 line.

2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1/ An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155), and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on normal hematopoietic stem cells (HSCs).

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy remains uncertain until clinical trials are undertaken in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia et al. used the knockout mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knockout mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cellular differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please click [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| here] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. found that the epithelial-mesenchymal interactions in the development of the Wolffian duct and testis cord are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins, when mutated, become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin ,rather than the bacterial cell numbers, is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents, BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab, on the mice containing EGFR mutated lung tumors. It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''', which has been studied to assist in generating antibody and CD4 T helper cell responses. This process was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Haploid:''' A set of chromosomes containing only one member of each chromosome pair. The sperm and egg are haploid.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Mutation:''' is a randomly derived change to the nucleotide sequence of the genetic material of an organism.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Oncogenic:''' An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Renaturation:''' The process by which proteins or complementary strands of nucleic acids reform their native conformations.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Telocentric:''' a chromosome like a straight rod with the centromere in terminal position.

'''Transgenic:'''A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered using genetic engineering techniques.

'''Transposition:''' is a kind of mutation in which a chromosomal segment is transfered to a new position on the same or another chromosome.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Shiro, I., Meytha, M., Cristina, V., Karen, E., Walid, K., Howard, G. (2006). An immortalized drug-resistant cell line established from 12-13-day mouse embryos for the propagation of human embryonic stem cells. ''Differentiation''. Accessed from http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KJLDc4JX2vKFKSQbLw7SSJTx2pGy4dMvGQJ9zpGxDdZ5hN1YyC6H!-2135654213!181195629!8091!-1

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*Geneall. ''Dame Anne Laura Dorinthea McLaren'', retrieved September 21, 2009. http://www.geneall.net/U/per_page.php?id=557208

*Harvard University. ''Howard Green, M.D.'', retrieved September 24, 2009. http://cellbio.med.harvard.edu/faculty/green/index.html

*Institute of Medical Biology. ''Davor Solter'', retrieved October 12, 2009. http://www.imb.a-star.edu.sg/Default.aspx?tabid=224

*International Knockout Mouse Consortium. ''About the International Knockout Mouse Consortium'', retrieved September 19, 2009.

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Memorial University. ''Oration honouring Wesley Whitten'', retrieved September 11, 2009. http://www.mun.ca/marcomm/gazette/2000-2001/june14/convocation8.html

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*National Institute of Health Record. ''NIDCR Team Creates Mouse Model of Disease'', retrieved September 19, 2009. http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*University of Iowa : College of Liberal Arts and Sciences. ''Alumni Fellows'', retrieved September 26, 2009. http://images.google.com.au/imgres?imgurl=http://www.clas.uiowa.edu/_includes/images/alumni/beatrice.jpg&imgrefurl=http://www.clas.uiowa.edu/alumni/programs/fellows/2002/&usg=__ZTVwhRDWmWlpQWiTgm7QPANk0ow=&h=218&w=182&sz=10&hl=en&start=2&sig2=WxT11tEDMuSTsbeT1PzXjQ&um=1&tbnid=7WxPUu34U_wdOM:&tbnh=107&tbnw=89&prev=/images%3Fq%3Dbeatrice%2Bmintz%26hl%3Den%26sa%3DN%26um%3D1&ei=ECy2Sp_JKMiGkAX9k9XBCw

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

*Wikipedia. ''Gregor Mendel'', retrieved September 20, 2009. http://en.wikipedia.org/wiki/File:Gregor_Mendel.png

*Wikipedia. ''Rudolf Jaenisch'', retrieved September 17, 2009. http://en.wikipedia.org/wiki/File:Jaenisch_2003_by_Sam_Ogden.jpg

{{Template:Projects09}}
[[Category:Mouse]]

2009 Group Project 4

2009-10-14T21:30:33Z

Z3254857: /* History of the use of the Mouse Embryo Model */

== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Is a small organism which can be easily maintained
*Is not expensive
----

===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

Link to photo of Whesley Whitten: [http://www.mun.ca/marcomm/gazette/2000-2001/june14/convocation8.html]

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

Link to photo of Anne McLaren: [http://www.geneall.net/U/per_page.php?id=557208]

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

Link to photo of Beatrice Mintz: [http://images.google.com.au/imgres?imgurl=http://www.clas.uiowa.edu/_includes/images/alumni/beatrice.jpg&imgrefurl=http://www.clas.uiowa.edu/alumni/programs/fellows/2002/&usg=__ZTVwhRDWmWlpQWiTgm7QPANk0ow=&h=218&w=182&sz=10&hl=en&start=2&sig2=WxT11tEDMuSTsbeT1PzXjQ&um=1&tbnid=7WxPUu34U_wdOM:&tbnh=107&tbnw=89&prev=/images%3Fq%3Dbeatrice%2Bmintz%26hl%3Den%26sa%3DN%26um%3D1&ei=ECy2Sp_JKMiGkAX9k9XBCw]

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

The mouse model has been used significantly in past scientific experiments. The mouse has many beneficial qualities which allow it to be easily manipulate and studied. One example includes its ability to reproduce and embryological development.

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Fingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development, so far, a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development click the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm. The 26 Theiler stages are covered within 18 days, while stages 27 and 28 are covered during day 19 and the days after birth.
{{Insert timeline}}
----

===Genetics===
[[image:800px-Knockout_Mice5006-300.jpg|thumb|300px|right|Knockout Mice]]
The mouse is extensively used in experimental models because of its genome and its ability to be manipulated and studied.

'''Genome'''

In late 2002 the sequencing of the mouse genome was completed. Scientists have discovered that the haploid genome for the mouse is about 3 billion bases long having a total of 3000 Mb distributed over 20 chromosomes. The size of the mouse genome is closely related to the human genome size. Scientists estimate the gene count of the mouse genome to be 23,786 genes when compared to humans having 23,686 genes, a degree of size similarity can be shown.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino.
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).
[[image:Nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome. Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.

Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function. However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.

[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve in mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues [http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm] created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:

1.Supports the multiplication of the H9 cells better than the 3T3 line.

2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1/ An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155), and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on normal hematopoietic stem cells (HSCs).

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy remains uncertain until clinical trials are undertaken in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia et al. used the knockout mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knockout mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cellular differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please click [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| here] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. found that the epithelial-mesenchymal interactions in the development of the Wolffian duct and testis cord are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins, when mutated, become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin ,rather than the bacterial cell numbers, is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents, BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab, on the mice containing EGFR mutated lung tumors. It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''', which has been studied to assist in generating antibody and CD4 T helper cell responses. This process was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Haploid:''' A set of chromosomes containing only one member of each chromosome pair. The sperm and egg are haploid.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Mutation:''' is a randomly derived change to the nucleotide sequence of the genetic material of an organism.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Oncogenic:''' An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Renaturation:''' The process by which proteins or complementary strands of nucleic acids reform their native conformations.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Telocentric:''' a chromosome like a straight rod with the centromere in terminal position.

'''Transgenic:'''A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered using genetic engineering techniques.

'''Transposition:''' is a kind of mutation in which a chromosomal segment is transfered to a new position on the same or another chromosome.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

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*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

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*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

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*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

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* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

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*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

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*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*University of Iowa : College of Liberal Arts and Sciences. ''Alumni Fellows'', retrieved September 26, 2009. http://images.google.com.au/imgres?imgurl=http://www.clas.uiowa.edu/_includes/images/alumni/beatrice.jpg&imgrefurl=http://www.clas.uiowa.edu/alumni/programs/fellows/2002/&usg=__ZTVwhRDWmWlpQWiTgm7QPANk0ow=&h=218&w=182&sz=10&hl=en&start=2&sig2=WxT11tEDMuSTsbeT1PzXjQ&um=1&tbnid=7WxPUu34U_wdOM:&tbnh=107&tbnw=89&prev=/images%3Fq%3Dbeatrice%2Bmintz%26hl%3Den%26sa%3DN%26um%3D1&ei=ECy2Sp_JKMiGkAX9k9XBCw

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

*Wikipedia. ''Gregor Mendel'', retrieved September 20, 2009. http://en.wikipedia.org/wiki/File:Gregor_Mendel.png

*Wikipedia. ''Rudolf Jaenisch'', retrieved September 17, 2009. http://en.wikipedia.org/wiki/File:Jaenisch_2003_by_Sam_Ogden.jpg

{{Template:Projects09}}
[[Category:Mouse]]

2009 Group Project 4

2009-10-14T21:29:51Z

Z3254857: /* History of the use of the Mouse Embryo Model */

== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Is a small organism which can be easily maintained
*Is not expensive
----

===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

Link to photo of Whesley Whitten: [http://www.mun.ca/marcomm/gazette/2000-2001/june14/convocation8.html]

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

Link to photo of Anne McLaren: [http://www.geneall.net/U/per_page.php?id=557208]

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

The mouse model has been used significantly in past scientific experiments. The mouse has many beneficial qualities which allow it to be easily manipulate and studied. One example includes its ability to reproduce and embryological development.

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Fingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development, so far, a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development click the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm. The 26 Theiler stages are covered within 18 days, while stages 27 and 28 are covered during day 19 and the days after birth.
{{Insert timeline}}
----

===Genetics===
[[image:800px-Knockout_Mice5006-300.jpg|thumb|300px|right|Knockout Mice]]
The mouse is extensively used in experimental models because of its genome and its ability to be manipulated and studied.

'''Genome'''

In late 2002 the sequencing of the mouse genome was completed. Scientists have discovered that the haploid genome for the mouse is about 3 billion bases long having a total of 3000 Mb distributed over 20 chromosomes. The size of the mouse genome is closely related to the human genome size. Scientists estimate the gene count of the mouse genome to be 23,786 genes when compared to humans having 23,686 genes, a degree of size similarity can be shown.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino.
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).
[[image:Nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome. Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.

Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function. However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.

[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve in mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues [http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm] created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:

1.Supports the multiplication of the H9 cells better than the 3T3 line.

2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1/ An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155), and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on normal hematopoietic stem cells (HSCs).

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy remains uncertain until clinical trials are undertaken in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia et al. used the knockout mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knockout mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cellular differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please click [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| here] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. found that the epithelial-mesenchymal interactions in the development of the Wolffian duct and testis cord are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins, when mutated, become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin ,rather than the bacterial cell numbers, is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents, BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab, on the mice containing EGFR mutated lung tumors. It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''', which has been studied to assist in generating antibody and CD4 T helper cell responses. This process was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Haploid:''' A set of chromosomes containing only one member of each chromosome pair. The sperm and egg are haploid.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Mutation:''' is a randomly derived change to the nucleotide sequence of the genetic material of an organism.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Oncogenic:''' An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Renaturation:''' The process by which proteins or complementary strands of nucleic acids reform their native conformations.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Telocentric:''' a chromosome like a straight rod with the centromere in terminal position.

'''Transgenic:'''A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered using genetic engineering techniques.

'''Transposition:''' is a kind of mutation in which a chromosomal segment is transfered to a new position on the same or another chromosome.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Shiro, I., Meytha, M., Cristina, V., Karen, E., Walid, K., Howard, G. (2006). An immortalized drug-resistant cell line established from 12-13-day mouse embryos for the propagation of human embryonic stem cells. ''Differentiation''. Accessed from http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KJLDc4JX2vKFKSQbLw7SSJTx2pGy4dMvGQJ9zpGxDdZ5hN1YyC6H!-2135654213!181195629!8091!-1

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*Geneall. ''Dame Anne Laura Dorinthea McLaren'', retrieved September 21, 2009. http://www.geneall.net/U/per_page.php?id=557208

*Harvard University. ''Howard Green, M.D.'', retrieved September 24, 2009. http://cellbio.med.harvard.edu/faculty/green/index.html

*Institute of Medical Biology. ''Davor Solter'', retrieved October 12, 2009. http://www.imb.a-star.edu.sg/Default.aspx?tabid=224

*International Knockout Mouse Consortium. ''About the International Knockout Mouse Consortium'', retrieved September 19, 2009.

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Memorial University. ''Oration honouring Wesley Whitten'', retrieved September 11, 2009. http://www.mun.ca/marcomm/gazette/2000-2001/june14/convocation8.html

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*National Institute of Health Record. ''NIDCR Team Creates Mouse Model of Disease'', retrieved September 19, 2009. http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*University of Iowa : College of Liberal Arts and Sciences. ''Alumni Fellows'', retrieved September 26, 2009. http://images.google.com.au/imgres?imgurl=http://www.clas.uiowa.edu/_includes/images/alumni/beatrice.jpg&imgrefurl=http://www.clas.uiowa.edu/alumni/programs/fellows/2002/&usg=__ZTVwhRDWmWlpQWiTgm7QPANk0ow=&h=218&w=182&sz=10&hl=en&start=2&sig2=WxT11tEDMuSTsbeT1PzXjQ&um=1&tbnid=7WxPUu34U_wdOM:&tbnh=107&tbnw=89&prev=/images%3Fq%3Dbeatrice%2Bmintz%26hl%3Den%26sa%3DN%26um%3D1&ei=ECy2Sp_JKMiGkAX9k9XBCw

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

*Wikipedia. ''Gregor Mendel'', retrieved September 20, 2009. http://en.wikipedia.org/wiki/File:Gregor_Mendel.png

*Wikipedia. ''Rudolf Jaenisch'', retrieved September 17, 2009. http://en.wikipedia.org/wiki/File:Jaenisch_2003_by_Sam_Ogden.jpg

{{Template:Projects09}}
[[Category:Mouse]]

2009 Group Project 4

2009-10-14T21:26:59Z

Z3254857: /* History of the use of the Mouse Embryo Model */

== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Is a small organism which can be easily maintained
*Is not expensive
----

===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten [http://www.mun.ca/marcomm/gazette/2000-2001/june14/convocation8.html](1918-), Australian Veterinary Scientist'''

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

The mouse model has been used significantly in past scientific experiments. The mouse has many beneficial qualities which allow it to be easily manipulate and studied. One example includes its ability to reproduce and embryological development.

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Fingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development, so far, a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development click the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm. The 26 Theiler stages are covered within 18 days, while stages 27 and 28 are covered during day 19 and the days after birth.
{{Insert timeline}}
----

===Genetics===
[[image:800px-Knockout_Mice5006-300.jpg|thumb|300px|right|Knockout Mice]]
The mouse is extensively used in experimental models because of its genome and its ability to be manipulated and studied.

'''Genome'''

In late 2002 the sequencing of the mouse genome was completed. Scientists have discovered that the haploid genome for the mouse is about 3 billion bases long having a total of 3000 Mb distributed over 20 chromosomes. The size of the mouse genome is closely related to the human genome size. Scientists estimate the gene count of the mouse genome to be 23,786 genes when compared to humans having 23,686 genes, a degree of size similarity can be shown.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino.
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).
[[image:Nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome. Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.

Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function. However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.

[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve in mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues [http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm] created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:

1.Supports the multiplication of the H9 cells better than the 3T3 line.

2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1/ An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155), and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on normal hematopoietic stem cells (HSCs).

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy remains uncertain until clinical trials are undertaken in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia et al. used the knockout mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knockout mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cellular differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please click [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| here] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. found that the epithelial-mesenchymal interactions in the development of the Wolffian duct and testis cord are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins, when mutated, become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin ,rather than the bacterial cell numbers, is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents, BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab, on the mice containing EGFR mutated lung tumors. It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''', which has been studied to assist in generating antibody and CD4 T helper cell responses. This process was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Haploid:''' A set of chromosomes containing only one member of each chromosome pair. The sperm and egg are haploid.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Mutation:''' is a randomly derived change to the nucleotide sequence of the genetic material of an organism.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Oncogenic:''' An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Renaturation:''' The process by which proteins or complementary strands of nucleic acids reform their native conformations.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Telocentric:''' a chromosome like a straight rod with the centromere in terminal position.

'''Transgenic:'''A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered using genetic engineering techniques.

'''Transposition:''' is a kind of mutation in which a chromosomal segment is transfered to a new position on the same or another chromosome.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Shiro, I., Meytha, M., Cristina, V., Karen, E., Walid, K., Howard, G. (2006). An immortalized drug-resistant cell line established from 12-13-day mouse embryos for the propagation of human embryonic stem cells. ''Differentiation''. Accessed from http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KJLDc4JX2vKFKSQbLw7SSJTx2pGy4dMvGQJ9zpGxDdZ5hN1YyC6H!-2135654213!181195629!8091!-1

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*Geneall. ''Dame Anne Laura Dorinthea McLaren'', retrieved September 21, 2009. http://www.geneall.net/U/per_page.php?id=557208

*Harvard University. ''Howard Green, M.D.'', retrieved September 24, 2009. http://cellbio.med.harvard.edu/faculty/green/index.html

*Institute of Medical Biology. ''Davor Solter'', retrieved October 12, 2009. http://www.imb.a-star.edu.sg/Default.aspx?tabid=224

*International Knockout Mouse Consortium. ''About the International Knockout Mouse Consortium'', retrieved September 19, 2009.

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Memorial University. ''Oration honouring Wesley Whitten'', retrieved September 11, 2009. http://www.mun.ca/marcomm/gazette/2000-2001/june14/convocation8.html

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*National Institute of Health Record. ''NIDCR Team Creates Mouse Model of Disease'', retrieved September 19, 2009. http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*University of Iowa : College of Liberal Arts and Sciences. ''Alumni Fellows'', retrieved September 26, 2009. http://images.google.com.au/imgres?imgurl=http://www.clas.uiowa.edu/_includes/images/alumni/beatrice.jpg&imgrefurl=http://www.clas.uiowa.edu/alumni/programs/fellows/2002/&usg=__ZTVwhRDWmWlpQWiTgm7QPANk0ow=&h=218&w=182&sz=10&hl=en&start=2&sig2=WxT11tEDMuSTsbeT1PzXjQ&um=1&tbnid=7WxPUu34U_wdOM:&tbnh=107&tbnw=89&prev=/images%3Fq%3Dbeatrice%2Bmintz%26hl%3Den%26sa%3DN%26um%3D1&ei=ECy2Sp_JKMiGkAX9k9XBCw

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

*Wikipedia. ''Gregor Mendel'', retrieved September 20, 2009. http://en.wikipedia.org/wiki/File:Gregor_Mendel.png

*Wikipedia. ''Rudolf Jaenisch'', retrieved September 17, 2009. http://en.wikipedia.org/wiki/File:Jaenisch_2003_by_Sam_Ogden.jpg

{{Template:Projects09}}
[[Category:Mouse]]

2009 Group Project 4

2009-10-14T21:26:20Z

Z3254857: /* Current Research */

== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Is a small organism which can be easily maintained
*Is not expensive
----

===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

The mouse model has been used significantly in past scientific experiments. The mouse has many beneficial qualities which allow it to be easily manipulate and studied. One example includes its ability to reproduce and embryological development.

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Fingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development, so far, a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development click the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm. The 26 Theiler stages are covered within 18 days, while stages 27 and 28 are covered during day 19 and the days after birth.
{{Insert timeline}}
----

===Genetics===
[[image:800px-Knockout_Mice5006-300.jpg|thumb|300px|right|Knockout Mice]]
The mouse is extensively used in experimental models because of its genome and its ability to be manipulated and studied.

'''Genome'''

In late 2002 the sequencing of the mouse genome was completed. Scientists have discovered that the haploid genome for the mouse is about 3 billion bases long having a total of 3000 Mb distributed over 20 chromosomes. The size of the mouse genome is closely related to the human genome size. Scientists estimate the gene count of the mouse genome to be 23,786 genes when compared to humans having 23,686 genes, a degree of size similarity can be shown.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino.
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).
[[image:Nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome. Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.

Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function. However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.

[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve in mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues [http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm] created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:

1.Supports the multiplication of the H9 cells better than the 3T3 line.

2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1/ An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155), and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on normal hematopoietic stem cells (HSCs).

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy remains uncertain until clinical trials are undertaken in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia et al. used the knockout mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knockout mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cellular differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please click [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| here] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. found that the epithelial-mesenchymal interactions in the development of the Wolffian duct and testis cord are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins, when mutated, become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin ,rather than the bacterial cell numbers, is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents, BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab, on the mice containing EGFR mutated lung tumors. It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''', which has been studied to assist in generating antibody and CD4 T helper cell responses. This process was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Haploid:''' A set of chromosomes containing only one member of each chromosome pair. The sperm and egg are haploid.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Mutation:''' is a randomly derived change to the nucleotide sequence of the genetic material of an organism.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Oncogenic:''' An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Renaturation:''' The process by which proteins or complementary strands of nucleic acids reform their native conformations.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Telocentric:''' a chromosome like a straight rod with the centromere in terminal position.

'''Transgenic:'''A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered using genetic engineering techniques.

'''Transposition:''' is a kind of mutation in which a chromosomal segment is transfered to a new position on the same or another chromosome.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Shiro, I., Meytha, M., Cristina, V., Karen, E., Walid, K., Howard, G. (2006). An immortalized drug-resistant cell line established from 12-13-day mouse embryos for the propagation of human embryonic stem cells. ''Differentiation''. Accessed from http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KJLDc4JX2vKFKSQbLw7SSJTx2pGy4dMvGQJ9zpGxDdZ5hN1YyC6H!-2135654213!181195629!8091!-1

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*Geneall. ''Dame Anne Laura Dorinthea McLaren'', retrieved September 21, 2009. http://www.geneall.net/U/per_page.php?id=557208

*Harvard University. ''Howard Green, M.D.'', retrieved September 24, 2009. http://cellbio.med.harvard.edu/faculty/green/index.html

*Institute of Medical Biology. ''Davor Solter'', retrieved October 12, 2009. http://www.imb.a-star.edu.sg/Default.aspx?tabid=224

*International Knockout Mouse Consortium. ''About the International Knockout Mouse Consortium'', retrieved September 19, 2009.

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Memorial University. ''Oration honouring Wesley Whitten'', retrieved September 11, 2009. http://www.mun.ca/marcomm/gazette/2000-2001/june14/convocation8.html

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*National Institute of Health Record. ''NIDCR Team Creates Mouse Model of Disease'', retrieved September 19, 2009. http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*University of Iowa : College of Liberal Arts and Sciences. ''Alumni Fellows'', retrieved September 26, 2009. http://images.google.com.au/imgres?imgurl=http://www.clas.uiowa.edu/_includes/images/alumni/beatrice.jpg&imgrefurl=http://www.clas.uiowa.edu/alumni/programs/fellows/2002/&usg=__ZTVwhRDWmWlpQWiTgm7QPANk0ow=&h=218&w=182&sz=10&hl=en&start=2&sig2=WxT11tEDMuSTsbeT1PzXjQ&um=1&tbnid=7WxPUu34U_wdOM:&tbnh=107&tbnw=89&prev=/images%3Fq%3Dbeatrice%2Bmintz%26hl%3Den%26sa%3DN%26um%3D1&ei=ECy2Sp_JKMiGkAX9k9XBCw

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

*Wikipedia. ''Gregor Mendel'', retrieved September 20, 2009. http://en.wikipedia.org/wiki/File:Gregor_Mendel.png

*Wikipedia. ''Rudolf Jaenisch'', retrieved September 17, 2009. http://en.wikipedia.org/wiki/File:Jaenisch_2003_by_Sam_Ogden.jpg

{{Template:Projects09}}
[[Category:Mouse]]

2009 Group Project 4

2009-10-14T21:23:09Z

Z3254857: /* Current Research */

== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Is a small organism which can be easily maintained
*Is not expensive
----

===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

The mouse model has been used significantly in past scientific experiments. The mouse has many beneficial qualities which allow it to be easily manipulate and studied. One example includes its ability to reproduce and embryological development.

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Fingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development, so far, a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development click the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm. The 26 Theiler stages are covered within 18 days, while stages 27 and 28 are covered during day 19 and the days after birth.
{{Insert timeline}}
----

===Genetics===
[[image:800px-Knockout_Mice5006-300.jpg|thumb|300px|right|Knockout Mice]]
The mouse is extensively used in experimental models because of its genome and its ability to be manipulated and studied.

'''Genome'''

In late 2002 the sequencing of the mouse genome was completed. Scientists have discovered that the haploid genome for the mouse is about 3 billion bases long having a total of 3000 Mb distributed over 20 chromosomes. The size of the mouse genome is closely related to the human genome size. Scientists estimate the gene count of the mouse genome to be 23,786 genes when compared to humans having 23,686 genes, a degree of size similarity can be shown.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino.
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).
[[image:Nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome. Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.

Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function. However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.

[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve in mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===
[[image:NIDCR.jpg|thumb|200px|right|Members of NIDCR]]

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues [http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm] created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:

1.Supports the multiplication of the H9 cells better than the 3T3 line.

2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1/ An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155), and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on normal hematopoietic stem cells (HSCs).

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy remains uncertain until clinical trials are undertaken in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia et al. used the knockout mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knockout mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cellular differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please click [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| here] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. found that the epithelial-mesenchymal interactions in the development of the Wolffian duct and testis cord are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins, when mutated, become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin ,rather than the bacterial cell numbers, is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents, BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab, on the mice containing EGFR mutated lung tumors. It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''', which has been studied to assist in generating antibody and CD4 T helper cell responses. This process was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Haploid:''' A set of chromosomes containing only one member of each chromosome pair. The sperm and egg are haploid.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Mutation:''' is a randomly derived change to the nucleotide sequence of the genetic material of an organism.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Oncogenic:''' An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Renaturation:''' The process by which proteins or complementary strands of nucleic acids reform their native conformations.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Telocentric:''' a chromosome like a straight rod with the centromere in terminal position.

'''Transgenic:'''A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered using genetic engineering techniques.

'''Transposition:''' is a kind of mutation in which a chromosomal segment is transfered to a new position on the same or another chromosome.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Shiro, I., Meytha, M., Cristina, V., Karen, E., Walid, K., Howard, G. (2006). An immortalized drug-resistant cell line established from 12-13-day mouse embryos for the propagation of human embryonic stem cells. ''Differentiation''. Accessed from http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KJLDc4JX2vKFKSQbLw7SSJTx2pGy4dMvGQJ9zpGxDdZ5hN1YyC6H!-2135654213!181195629!8091!-1

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*Geneall. ''Dame Anne Laura Dorinthea McLaren'', retrieved September 21, 2009. http://www.geneall.net/U/per_page.php?id=557208

*Harvard University. ''Howard Green, M.D.'', retrieved September 24, 2009. http://cellbio.med.harvard.edu/faculty/green/index.html

*Institute of Medical Biology. ''Davor Solter'', retrieved October 12, 2009. http://www.imb.a-star.edu.sg/Default.aspx?tabid=224

*International Knockout Mouse Consortium. ''About the International Knockout Mouse Consortium'', retrieved September 19, 2009.

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Memorial University. ''Oration honouring Wesley Whitten'', retrieved September 11, 2009. http://www.mun.ca/marcomm/gazette/2000-2001/june14/convocation8.html

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*National Institute of Health Record. ''NIDCR Team Creates Mouse Model of Disease'', retrieved September 19, 2009. http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*University of Iowa : College of Liberal Arts and Sciences. ''Alumni Fellows'', retrieved September 26, 2009. http://images.google.com.au/imgres?imgurl=http://www.clas.uiowa.edu/_includes/images/alumni/beatrice.jpg&imgrefurl=http://www.clas.uiowa.edu/alumni/programs/fellows/2002/&usg=__ZTVwhRDWmWlpQWiTgm7QPANk0ow=&h=218&w=182&sz=10&hl=en&start=2&sig2=WxT11tEDMuSTsbeT1PzXjQ&um=1&tbnid=7WxPUu34U_wdOM:&tbnh=107&tbnw=89&prev=/images%3Fq%3Dbeatrice%2Bmintz%26hl%3Den%26sa%3DN%26um%3D1&ei=ECy2Sp_JKMiGkAX9k9XBCw

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

*Wikipedia. ''Gregor Mendel'', retrieved September 20, 2009. http://en.wikipedia.org/wiki/File:Gregor_Mendel.png

*Wikipedia. ''Rudolf Jaenisch'', retrieved September 17, 2009. http://en.wikipedia.org/wiki/File:Jaenisch_2003_by_Sam_Ogden.jpg

{{Template:Projects09}}
[[Category:Mouse]]

Talk:2009 Group Project 4

2009-10-14T21:22:26Z

Z3254857: /* Changes made */

== Project Updates ==
--[[User:Z3283499|Antonio Lee]] 10:57, 2 October 2009 (EST) Hi everyone, I will be working with you during the Lab10 Tutorial and here is the news link and PDF of the manuscript for your group exercise. I encourage you to read the paper before the tutorial. Also, please indicate next to the questions below (using either your initials or student number) which one of the four questions you wish to address.
:'''Group 4 :''' [http://www.scientificamerican.com/article.cfm?id=stem-cells-from-fat-cells '''Induced Pluripotent Stem Cells Created from Fat Cells'''] in Scientific American Published online 8 September 2009 [[Media:ANAT2341_Lab10_2009_Group 4 Reading.pdf|Manuscript (PDF): Feeder-free derivation of induced pluripotent stem cells from adult human adipose stem cells]]

:Question 1. What is the background to the existing problem / disease condition?--[[User:Z3252340|Emily Wong]] 13:41, 8 October 2009 (EST)
:Question 2. What approach / method did the research team take to tackle / improve the problem? --[[User:Z3252231|Angama Yaquobi]] 19:27, 7 October 2009 (EST)(Angama Yaquobi)
:Question 3. What was the breakthrough / major advancement OR failure / drawback? and why might this be of significance?--[[User:Z3224449|Elide Newton]] 13:43, 8 October 2009 (EST)
:Question 4. What are the next steps in moving forward? What are the next or new hurdles to overcome?--[[User:Z3254857|Begum Sonmez]] 12:42, 8 October 2009 (EST)

==Constructive Criticism of Coordinator==
--[[User:S8600021|Mark Hill]] 08:07, 8 October 2009 (EST) The following comments are general in nature in no specific order, as it would be inappropriate to suggest specific changes and then assess the final project. Comments will be added during this week and you still have one week before final submission.

* The project has improved in content and layout from the original submission date.
* A general comment about images. When you click an image and it opens, the information below the image should have an explanation of what the image shows, a reference (if from a paper) and a link to the original source (if available) as well as copyright information.
* There are still issues related to page design with large white spaces visible.
* [[:File:Mice_expressing_GFP.jpg]] What is the original source of this image? Do you have permission to reuse?
* [[:File:Transgenicmouse.jpg]] © 2009 Nikon Instruments Inc. can you reuse?
* [[:File:Genetics of laboratory rodents.jpg]] What is this transgenic mouse expression pattern showing?
* The Theiler images of embryo stages are useful to have, are they really all redrawn? I will be comparing these to the original online versions and they cannot be direct copies without permission.
* [[:File:Mouse_theiler_stage8.JPG]] Reichard's menbrane?
* Glossary still incomplete.
* Reference could be tidied up.

==Constructive Criticism of Peers==

--[[User:Z3218657|Sally Clarke]] 09:59, 1 October 2009 (EST)Well Done!

I'm just jumping straight into it..

- I Think the timeline stage is fantastic - the images and information are displayed really well

- the staging information is a little cramped and thrown in together - it doesn't flow very well and the images are all over the shop

- The history section has A LOT of information an images of the scientists, what they did and how they did it - great... i know this would have taken a lot of work but its a bit long. I think maybe making it into a timeline on different pages might help this.

- The headings and sub headings are really good and informative but there is a few formatting errors which is easy to fix

- The genetics sections is really good, nice and concise yet informative

Great assignment guys!

--[[User:Z3258567|Sando Rashed]] 09:12, 1 October 2009 (EST)hey wow lots of information in this page :D, well done with the effort use all put in it looks and sounds goood, few things im not sure if it was my computer but staging of embryonic development there was just a bunch of photos and they were crammed up and overlapping each other making it very hard to read use might want to cut down on the photos in that area or scale them down to make it easier to read. you have a lot of information in your history section its good that you have what they do and their contribution to make it look a bit better you might want to split it up into a 3 way table (name/what they do/how it helped) minimise the reading as i recall dr mark saying to much reading is not something he wants he wants something more appealing to him where he can lay in bed and mark it without falling asleep so a table would be good here. other than that its a great page :D well done hope use all do well!!

--[[User:Z3223194|Bronwyn Lewis-Jones]] 08:53, 1 October 2009 (EST) Congratulations on a great assignment. There are so many good things about this page. I think the biggest (and easiest) improvement to be made is to cut down on the amount of headings for the History and Current Research. The headings used such as "What did they do?" etc are helpful in showing the reader what exactly they are to understand from what is written, however they interrupt the flow and spread out the information so that it seems rather daunting. If you can summarise each section into a few sentences then I think that will not only reduce your contents section to a more useful size but also make the page more reader friendly. If you don't like that idea you could strike a happy medium by either having you "What did they do..." to bold instead of a heading or have (in bold or italics) a very short summary sentence under the name followed by a short few sentences. This would still give the reader an impression of what do get out of each section but would increase the flow inside and between notable researchers etc. Hope you find this helpful. :)

--[[User:Z3218146|Julianna Lam]] 01:31, 1 October 2009 (EST)
- the history section is TOO long ! the structure of the history section is good, i liked the whole idea of the sub headings ie ' what did he do?' but i think you guys included way too many people in there. the layout of the history section is not very neat and very inconsistent. you provided pictures of some people but didnt provide pictures of others. there are gaps everywhere and it just looks really messy.

- the stages and timeline parts are really good. the table looks really nice. and i especially like the pictures, very well labelled.

--[[User:Z3186093|Jenny Guy]] 18:46, 30 September 2009 (EST)

Improvements:
* The history is wayyyy too long. Seriously, there are too many sub sub sub headings. Cut it down and for each scientist make it a paragraph instead of so many dot points. I almost couldnt be bothered reading them all. Definitely not a good way to represent information. Looks as though you gave up on looking for pictures of the scientists. I would too if i had that many of them. Pick the main scientists that caused a breakthrough instead of listing all 1000 of them. Also, it is inconsistent if you did decide to keep the subsubsubsub headings as 'what he did', "what he found" and "what the importance" are generally all targeting the same question.
* I think you guys are confused as your information is conflicting. Humans have 23 pairs of chromosomes. In your introduction you state they humans and mice have the same number. However in the genetics it states that mice have 20pairs. What is true?
* There are a few gaps (large random spaces) in the genetics sections. Might want to format this a little.
* For the current research see the same massive point i mentioned first....
* Your referencing in the bibliography is inconsistent. Stick with one type of system, e.g. apa OR harvard. Some of the references aren't even referenced properly. You must reference websites.
* You haven't referenced ANY of you text. How do we know you havent just cut and paste? You need to either reference within the text (e.g. Andrews, E.A. (1895) states .....) or at the end of sentences/paragraphs with (Andrews 1895) or the number used in the bibliography.

--[[User:Z3255007|Sadaf Masood]] 15:43, 30 September 2009 (EST)Hey Group 4! Congrats on your great project guys! I have listed few points that might help:

1. Very well researched History section, lots of people doin lots of work..maybe you can make it a little short as its just a little too much info on them.

2. A bit more proper formatting, lots of gaps after every picture and table, maybe you can get rid of them

3. Timeline is great, just enough info to make sense and needed.

4. 'Why use of mouse is important?' this issue is well discussed. Great work!

5. Impressive hand drawn diagrams, any chances of making them a little larger on the main page? it would look really good!

6. Glossary is also needed...will make our life easier is understanding few words.

Rest is all well guys. The current research Section is awesome, very informative and lots of details. Its a great project guys...Best of Luck!!

--[[User:Z3218792|Gabriela Pinget]] 12:59, 30 September 2009 (EST) Hello! constructive criticism as follows:

- intro is a nice ease in but needs to be edited for grammar

- wow the history section is very well researched. I like that you've included so many contributors but are you sure you need to go into so much detail? It looks a little cluttered and detracts from the overall purpose of the assignment. Think about cutting down on it a little

- I really like the ''staging of embryonic development'' section! very engaging and well formatted! well done

-I also liked the timeline of development. I like that there was not too much information at each stage, but just enough to give a clear outline. Maybe a link to find out more would be useful

- genetics section is perfect

- again, the current research section is a little too spread out. The continuous "what did they do..." works well to begin with but after a while gets to be too much

Overall, a really nice looking page

--[[User:Z3295026|Joe Nassif]] 17:59, 29 September 2009 (EST)

Awesome looking wiki page, mouse group 4 an excellent assignment.

It is a really interesting reading and viewing your wiki page the content flow really well when reviewed.

1. The assignment is impressive it outlines the point with the use of sub headings which is always useful in the project as a referencing point.

2. (What did he do?) and (What did they find?) is a great way to state the history as it allows the reader to quickly get the brief information and understand it , also the illustrations throughout the assessment was great it referred to the text really well, which supported the info impressively. The hand drawn images in the (staging) and (timeline) sections were extremely great the detail was impressive.

3. Some ways to improve the assignment:
A) There are some unnecessary data throughout the project which are not relevant for example the ‘length of mouse embryo’ , removing this sections can truncate the assignment which would enhance the structure.

B) Current research information on the background of the research finders reveal great info on the development of the model usage, the findings and the relevance to human embryology have been summarized greatly.

C) The referencing need to be fixed in proper format. Visit : www.lc.unsw.edu.au/onlib/ref_apa.html for help with APA referencing

D) a glossary is needed to help the reader understand terms.

Overall a great project. The criteria was covered really well it, stated specfic topic in regards to the mouse and it embryonic developent which group 4 has summarised really well.

--[[User:Z3295026|Joe Nassif]] 17:59, 29 September 2009 (EST)

--[[User:Z3217015|Mitchell Mathieson]] 09:39, 25 September 2009 (EST)Page looks good. I liked how there was heaps of information on the genetics and the current research (however, this was a bit too spread out maybe). There seems to be a lot of gaps in the text, so the formatting could be maybe tightened up. The references maybe should be formatted better, and there is repeated information (tables and text for stages), but I really like how clicking the image goes to another page with more information...that is cool. The drawings are cute as well. Overall very good, I think formatting was the downfall from that, but the information is top notch.

--[[User:Z3126328|Jin Lee]] 16:42, 26 September 2009 (EST) hellow group4~ very impressive assignment guys!well done! I really enjoyed reading your assignment. it was easy to read and the information was relevant. However, I found the formatting of the images and texts were too sqeezy. may be resize the images and line up with the relevant information. Also, I think the reference needs to be looked after as well. Overall, the contents of the assignment is very useful and interesting.

--[[User:Z3187802|Vishnnu Shanmugam]] 20:02, 26 September 2009 (EST)Congratulations mouse group on an excellent assignment. It is a real joy to read. One of the best features of the assignment is how it gets straight to the point with the use of sub headings “What did he do?” & “What did they find?”. Even the images used throughout the text are interesting, especially the fully labeled hand drawn images in the “staging” and “timeline” sections. Some ways to improve the assignment:

-There are some unnecessary graphs in the assignment such as “the average length of mouse embryo”, “number of cells” and “number of somites”. These could perhaps be combined into a single graph. It will also reduce the congested appearance of the assignment as it seems too densely packed with no particular focus.

- In current research section, it is advisable to reduce the number of research and focus on just a few but provide more comprehensive information on the background of the research, the findings and the relevance to human embryology. It currently contains too many different types of research that have described very briefly.

- Edit the "content" section at the top of the page as it's length seems to be getting out of control. It is perhaps better to exclude the sub headings “What did he do?” & “What did they find?” in the contents.

- The referencing in the text need to be completed as there are some sections well referenced and others with no referencing. see www.lc.unsw.edu.au/onlib/ref_apa.html for help with APA referencing

- A Glossary would also complement the text.

Overall a classy project, only some changes necessary

--[[User:Z3126345|Gang Liu]] 16:49, 27 September 2009 (EST)This is one of the better wikipage i have seen so far. It demonstrates not only extended literature research skill, but also an in-depth understanding of the topic. The content of this page has been consistent throughout. In addition, paragraphs are straigtforward and concise, and make the point. Detailed texts with accessory graphics are appropriate in here. In paticular, history section. It describes the model use in terms of details of experiment, and results of experiment. Stages and timeline are very self-explanatory and visually enhanced.

This project can be improved by considering the following points.

*Lack of glossary list. Need to provide meaning of words such as "polyestrous", "oocyte", "Ectoderm", "endoderm", etc;

*Reformat stages section. I found this section a bit "busy". Might considering resize the pictures.

Last few words. I have learnt from this page that mouse has the same size genome as the human genome; Mouse genes can be easily manipulated and studied; Mouse a high degree of homogeny with humans. Well done!

--[[User:Z3217686|Thomas Dangerfield]] 14:12, 28 September 2009 (EST)Hey guys! Wow so much info first off! Not entirely sure we need to know about everyone involved in the history, maybe could have collaborated and joined people together or possibly even left certain people out. To me, the whole page is like how mark described, with everything all one great smudge of info with no real formatting or sequence or continuation. It was just kind of like an overload and reading it was a little difficult at some stages. Also corresponding the images in the timeline could have been included in the text.

Also I think your numbering of figures is a little off in the timeline section, with figures 1-4 on the right and then you have figures 4-7 describing stages 12-14. Just seems that there is two figure 4's for two different images.

Love the large amount of research and information, but could just work on your presentation and you'll do fine! Great work guys!

--[[User:Z3185685|Sumaiya Rahman]] 16:56, 28 September 2009 (EST) Hey guys! Overall a very nice assignment with a great deal of information! You can tell you guys did a lot of research. The contents are massive! Maybe you could cut this down and not use so many subheadings such as “what did they do?”, “what did they find?” and only have a subheading for each researcher. The introduction is well written. The history of model use has some really good information. My only criticism in this section is that there are a lot of gaps and blank spaces. You just need to delete all the spaces. The staging section showed a lot of research and effort. Well done!! The only thing is, is it a bit too much? There are a lot of tables and images that it was hard to keep track. Maybe this could be set out differently and made to look less busy. The timeline of development is fantastic and set out really well. It is very easy to understand and the drawings are great! Once again the current research is very spread out with lots of spaces. Also adding a glossary may help the readers in understanding the text. GREAT JOB!

--[[User:Z3215682|Carly Mooney]] 11:49, 29 September 2009 (EST)
I think all your material is there but the page layout needs work. Especially the history of the models use.
*The spacing and images are inconsistent. I liked the history of timeline section information and how it was presented, just the spacing of it all needs to be even.
*The stages of embryonic development was a little all over the place, and very daunting to look at.
*A glossary would help.
I think you guys did a really good job and just have to work on presentation.

--[[User:Z3220040|Joanne Raffel]] 16:14, 29 September 2009 (EST) Very impressive page, however it was very long!!! The introduction was very clear and concise. The history section was extremely long and poorly formatted, there were too many pictures with too little information, I would recommend cutting some of the images and just keeping the pictures of those who made a significant impact upon the mouse embryo, I also thought it was unneccessary to write after each subheading, what did he do and their result, I would prefer if it was just one paragraph. Your main heading were overshadowed by the subheadings and the rest of the text. There is a lot of information for the staging section, which is good however it can made it difficult to read, I would recommend having some of the information linked onto a separate page. The picture and format for the timeline section was exceptional however it lacked information, I also thought that it was irrelevent rewriting the timeline after the pictures, I would recommend including it with the picture rather than after it and the graph size made it seem insignificant. The genetics section was very extensive and I thought some of the information was better included with the current research. Similar to the history section, I thought the formatting of the current research section was very unorganised and too spaced out. Overall a very nice page.

----

--[[User:S8600021|Mark Hill]] 01:46, 8 September 2009 (EST) Well the content is there now, but what a mess, and I am not just talking about the formatting problem which can be easily fixed, you have no structure to your project, its not a matter of throwing everything at a wall and seeing what sticks. Work together for an integrated coverage. Timeline of development, is not the way to start your page with a huge table of data.

--[[User:S8600021|Mark Hill]] 08:43, 21 August 2009 (EST) OK guys, time to see some actual content uploaded on both your discussion and project pages.

* Timeline of Development - how long (Emily)
* Staging - are there species specific staging, what occurs when (Elide)
* History of Model Use - when was it first used, what embryology research (Begum)
* Genetics - chromosome number, sequencing (Angama)
* Current Embryology Research - research papers and findings (All)

Here is a link for timeline
[http://books.google.com.au/books?id=XLIarRWHikAC&pg=PT199&lpg=PT199&dq=mouse+embryo+development+timeline&source=bl&ots=fobLBRiacx&sig=cK4cuZah6Ksczs3o8v4NXQqoAyk&hl=en&ei=rGB6SvTHMMmIkAXB_piAAw&sa=X&oi=book_result&ct=result&resnum=3#v=onepage&q=&f=false
]

link for the mouse brain development timeline http://en.wikipedia.org/wiki/Mouse_brain_development_timeline

hey guys there is another interesting link about mouse development http://mouseatlas.caltech.edu/index_content.html

Hey Emily. The link below has a timeline that you can check out in your spare time. Begum.
[http://books.google.com.au/books?id=4juoa5xMs8oC&pg=PA31&lpg=PA31&dq=mouse+embryology&source=bl&ots=9tJAfRG4R6&sig=hjR5Zs-sL1sCW5FY8FnR5TMaUk0&hl=en&ei=LuuMSr_aCNjakAX714icDA&sa=X&oi=book_result&ct=result&resnum=9#v=onepage&q=mouse%20embryology&f=false]

Hi girls,
here is a link to a text book about mouse embryology it looks pretty good. hope it can help
[http://books.google.com.au/books?id=4juoa5xMs8oC&printsec=frontcover&dq=mouse+development&source=gbs_similarbooks_r&cad=2#v=onepage&q=mouse%20development&f=false]
let me know if the link doesnt work. Ive been working on the main page, so have a look and tell me what you think, Also what are we doing about references? If we have used information but put it in our own words do we need to put in text citations,or do we just reference the journal at the end? I just want to be very careful. Thanks!

Hey Elide, i think your work is looking really good. its very easy to read and understand. keep going!!!! emily

hey everyone,
I have uploaded some of my timeline work. I'm not sure if I've gone into to much detail or not and also on how is best to present the timeline. It is fairly basic and definately needs some work - especially on presentation, grammar, etc. let me know what you think.
Emily

good site for stages or timeline- atlas of pictures of stages- The Edinburgh Mouse Atlas Project [http://genex.hgu.mrc.ac.uk/]

Hello girls, it's Begum. I put some info under the history section. Wanted to let you all know that I've got a fair bit of info, and I will do my part as best as I can. Btw Emily, I think maybe dot from would be best for you, but if you can use those lines that I was talking to you about on Wednesday, that would be great...I know it's hard.

hey everyone, i have put some info under the genetics heading and some under research. I am still struggling to find the appropriate info related to the topic of genetics because there is alot of info abt the different types of stains used in labarotories but not the genetics. I emailed Dr.Hill and have asked him what to include in my section specifically,hopefully he will help. So far i have just started it needs alot of more work to be done,girls just read thru my section n leme know wt u think of it. have a nice weekend everyone. Angama.

Hi girls!
Begum, you history info is really good. If very interesting! I really like how you are doing it in order of dates of discovery and what they did, what they found etc! Cant wait to know more.
Angama, your doing well! it sounds like your finding the info hard to get. I'll keep an eye out for you! If your stuck on what you sound be doing then i might have a few ideas. I remember Mark Hill saying that you should compare the genome to the humans genome. so maybe if the genome is the same size as the humans, could you descibe similarities or differences? I know that there is a link to the mouse genome on the mouse web page he gave us ( next to the discussion link). Are you just ment to list the mouse genome sequence? could you go into what genes code what, eg which one codes for the sex linked gene, is it the X and Y gene etc? hopefully Mark gives you some ideas.
well as you might have noticed i've been adding to my stages. the only thing is im worried about there being too much info up there. basically ive tried to get all the info available included in my stages to make sure i cover everything, and then later i'll go over it all and edit and polish it up a bit. Ive done some drawings to the best of my ability, but i can scrap them if you all think they arnt professional enough. just thought i'd try to present the information differently. let me know if you think i'm including too much information. i think i'm having the same problem as you begum, there is lots of info! Elide

Thanks Elide. I'm trying. (Again, loved the artwork!)Btw, Emily, I had a think about your section and I think it might be too much 'clicking' back-and-forth if we link the displayed pic to the 'info' page. Don't stress, you've got the info (heaps which is excellent) but make sure you get some pictures soon so we can start drawing (I'm helping with the drawings as well ok). Mark said 'Nature' and 'Science' have useable images so lets make that our start.
BTW, I will be using the question mark symbol(???) so I don't forget to reference. Begum

Hey everyone, I have found an online text book. it has a chapter on genetics and history and a lot of other stuff. [http://books.google.com.au/books?id=Vt6nUmz1yEQC&pg=RA1-PA207&dq=mouse+development+anatomy&client=firefox-a#v=onepage&q=mouse%20development%20anatomy&f=false] Emily

Hey girls. If you've seen my section, the info is not on the main page, but linked to another page. I thought that it might make everything look more neat. I thought we could all do it like that. It's just an idea. Something different. Maybe we could have something on the main page (picture of a mouse). Your thoughts everybody? Begum

hey begum, ur work looks really good. i like the idea of linking the work to another page. - we don't have to worry about to much info being on the front page and it gives people to option of viewing the work if they want to. ive been working on drawings, i'll show them to you next week but am not sure how to upload them at the moment. Emily

Thanks! That sounds great that you like the idea. About the photos that you are drawing, if there by hand, you can scan them somehow. But overall,
1. click 'Upload File' on the left hand side of this page
2. New page comes up: click 'Browse' and choose your file that you want to upload.
3. Name it (under the Browse button)
NOTE: write down what you named the file as because like Elide says "...it's going to be lost in space!..."
4. Write down info/comments (like who is the author (YOU), and if the drawing is based on a picture)
5. UPLOAD!
6. Go to your section and just normally type this down to the area you want the picture to be seen:
[[image:THE NAME THAT YOU SAVED THE FILE UNDER.jpg|thumb|200px|right|WHAT YOU WANT THE FILE NAME TO VISUALLY COME UP AS]]

Your thoughts Angama and Elide? (about the linking of our sections to separate pages?) Begum.

Oh and another thing:
What do you girls think about my page, I've got a heading for each DATE and underneath each there are further subheadings (e.g. 'What did he do?'. Should I change them to just text, I mean, does it look messy with sub-sub-headings? Begum.

wow girls! great work.. okay so i asked mark about a new page and he said to avoid it because our info is meant to be on our one page. he said if there is extra information on what we wanted to say but is too much for the main page then have a link to our discussion page. (which is what im going to do) Begum your new page is fantastic!! you have done lots of work! but why dont you just put it on our main page? also girls i think we are getting too carried away with info. just keep it simple! i'm sorry i havent been around this week to work on it but i plan to get going asap. just fixing up some things, summarising, writing introductions etc.
did you all read his note about slabbing info onto our page?? how about some introductions, and sentences to ease ourselves into the content. planning on trying to work on that now anyway..

also lets get the information flowing. why dont we go intro, history of model use, stages, timeline, genetics, then current use.. what do you all think?

hey, i thing that that sounds like a good, logical way to do the page. i've finished the drawings, just need to upload them. About the timeline information, is there anything specific that i should include. the stuff that is on the page is a little vague and so i need some advice as to what are key points that i should include. i know that the drawing are very simplistic, let me know wjat you think about them. ive put one up below. i just need a way to link it to text. emily

Thanks Elide. You know, I think that's a great idea. Have it all on one page, seems less 'diverging...', seems more COMPLETE. I love the ORDER as well. I'll fix all that up!

Hey girls, please have a look at what i've done on the timeline. the images are all hand drawn based upon the text: 'the house mouse'. if anyone could give me any ideas on how best to present the pictures - which would be better - next to or below the text? keep in mind that it is incomplete and there is an illustration for each day of development (i.e. 19 in total). if you think that is too many let me know, some may be similar to Elide's ones. Also, do you think i should put some colour into the drawings? Emily

I love your work Emily. All you need to do is put the info on the growth of the mouse that is on the main page, onto the page with the graph of the growth of the mouse embryo...we talked about that before any way-AND I think your parts finished! Begum.
Angama, I added something to the end of your section that I thought was interesting. Have a look. And are you mentioning manipulation and 'shut-down' of the genes in your section?? Begum.
To everyone, apparently ''Mus Musculus'' is the scientific name of the common house mouse, not the mouse. I was thinking of editing that.

HEY EVERYONE! well i've added in some pictures just to make it look more visual, change them if you have better ones.. and i'm going to be working on the current research section tommorow. oh i also added some graphs like we thought of for emilys section.. so i think my section is finished finally! what do you think? can i just say, I think the whole thing looks great! you girls have been a pleasure to work with! :) Thanks so much!!

hi girls, i am sorry..i have been very busy during the mid-sem break and i know we all had our exams and assignments due. but i was having some issues in my family and also the exams and assignments so didnt really had the chance to read wat u girls have got on the main page. i just finished reading thru it and it looks amazing..WELL DONE GIRLS!! you all have done a marvellous job...Eldie and Begum thanks for suggesting some main points to add for the genetics.i am currently working on it.. hopefully tonight i will have all the information on the page..Begum i love how you have presented alot of info into a very easy and understandable way..it makes so much sense..n it looks very nice with the pictures. Eldie and Emily great amount of work and the pictures and the graphs are superb. i just had a look to other groups pages. n i think so far our page looks very interesting with concise info n amazing pictures. n Begum yes i read what you have added thanks for tht..i will cu girls around..gudluck everyone. cheers. Angama.

Girls can you please help me out.. i am so annoyed..
like rite now i was typing some info and when i clicked to save.
it says "conflict" so i think some one else is also editing
the page at the same time that i am. and i lost all my work..arghh..
so which means i have to type it all again.
is there any other way that it tells me that someone else
is also using it so i dont click on save or even preview
because when i do tht i lost all the work tht i had.
If anyone knows please let me know. thanks. Angama.

Current research : I have put some information in the current research part. not sure where they should be put. Begum, as discussed you can edit it or place it in its appropriate place.

Don't stress Angama at all, now you know, it will be over soon. Uploading it easy:

1. click 'Upload File' on the left hand side of this page

2. New page comes up: click 'Browse' and choose your file that you want to upload.

3. Name it (under the Browse button) NOTE: write down what you named the file as because like Elide says "...it's going to be lost in space!..."

4. Write down info/comments (like who is the author (YOU), and if the drawing is based on a picture)

5. UPLOAD! 6. Go to your section and just normally type this down to the area you want the picture to be seen:

It's easier than it is typed! Of you still have problems I will be at the embryo lab, of there is exams there the ANAT LAB opposite to it, if not Level 3 library computers.

[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19538749| maternal diabetes alters transcriptional programs in the developing embryo], [http://www.ncbi.nlm.nih.gov/pubmed/19414407?ordinalpos=35&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum|Abnormal mammary gland development in MMTV-CBLC transgenic mouse], [http://www.ncbi.nlm.nih.gov/pubmed/19394325?ordinalpos=40&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum|Sonic hedgehog signalling inhibits palatogenesis and arrests tooth development in a mouse model of the nevoid basal cell carcinoma syndrome.], [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=55&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum| Fibroblast growth factor 18 gives growth and directional cues to airway cartilage.]

Hi girls, i think i have completed my section. could you all please just read thru it and leme know wat you think of it. i did it to the best of my ability. Hopefully you will all like it if you girls think therez anything more to add or to delete leme know..thanks. gudluck girls. Angama.

Angama your work is fantastic! Thanks so much! im sorry i wasnt around to help you with the problems. hope it went okay. your info is perfect! im very happy with our page! lets hope everyone else is :)

I love it Angama, good work! And the pictures you uploaded are very interesting. Cool. Awesome. Your done!! Begum.

Thanks Begum :) Girls gudluck and cu all tomorrow. Angama.

== Discussion after peer assessment and constructive criticism ==

Hi girls,
Ive started making some changes to the page based on the comments recieved.
Note i've also started a glossary of terms. Also many of our comments regarded our references,so It would be great if we could all reference the same, lets say APA because this is the most common way for referencing. I have gone through our references and tried to format them in APA. many are incomplete references so i have bolded the references that are missing detail. please if you all could complete your references that you added to the list. Also shall we number the references so we can include the numbers in the text as in text references? like foot note? what do you all think... there have been many comments on our current research page.. so how would you all like to fix it? I personally think its way too much. It seems to have accumulated heaps of info from when I last saw it. Is there anyway of summarising the current research info to focus more on how they are used rather than the institute and scientists involved. I think the most important info in this section is what mice are being used to discover currently and proof of the year of study. Cant wait to hear what you all think! Elide

one more thing.. ive tried to edit the contents, as one of our peers suggested, however i cant seem to edit it. do any of you know how to do this?
Elide

hey emily, i see you have reduced the heading in the contents!! thats great! i was just thinking that maybe we dont need so many headings in those 2 sections at all. what do you think about just making all the scientists and the names of people/ labs just in bold.?

Hi girls, have a look at the changes i have made to my section. let me know what you think. Emily

looks good!!
also girls could you please add words from your sections to the glossary, as that whole list is only from the staging section. thanks. elide

Hello girls. I will be re-formatting the history section in order to get rid of the 'gaps' that my peers have mentioned. Also, Elide mentioned yesterday that placing all the 'History' pictures towards the right-side of the page would look more neat, as well as add to the flow of the page. I think this is a great idea. Begum. Oh, and '''what do you guys think about taking out some information (findings)?''' Some students have mentioned that there is too much information/researchers.
And Elide, I'm might change the names of the researchers. like you said before, to bolded text. It would look much more neat. I might, also, '''apply this to the Genetics section. What do you all think?'''

'''Begum's Problem'''
Hey. I placed all pictures to the right-hand side (history section), but the pictures don't correspond well with the text. Any suggestions?? Should I than put the towards the left? Love the change to the timeline section Emily.

HEY BEGUM!!
so your problem.. I dont think the pictures need to match up because if they have a title of the person then the reader can find their picture. plus the comments are on the spaces and gaps between text, not the pictures.. so maybe just put them all underneath each other and even if they dont match up then at least the writing looks more organised. try making the images 200px and not so large and it could work better?. also the bit about taking out the headings in the genetics would be great!! bold would still look fine! goodluck! xox

--[[User:Z3254857|Begum Sonmez]] 14:54, 10 October 2009 (EST) '''TO ELIDE''': I was going to change the headings 'Reproduction' and 'Theiler Stages' under STAGES to bolded text. What do you think? Plus, like you said before, I'm on that ref. list, I will summarise the current research, and change those headings. If the HISTORY pictures match up to the the text, it would be more convenient for the viewer, don't you all think so??? However, the text would appear better the other way with the images al together on the right. Yes, I'll do that.

Hey '''Begum'''!
yes what a great idea about changing the headings in the staging section! the whole page needs to have the same structure throughout! I shall change them right now! :) i'm a little confused about the bit you said about what you said about the ref list. do you mean that you will fix yours? ive been through some of them and looked up the missing details. some are lacking their full reference though. but that would be so great if you could fix up your references. i think the ones in bold are the ones still needing work, but correct the others if you think they arent finished.
well i think the history section looks great! even though the pictures dont match up, they are still there and they look neat and have the same format as the rest of the page. and even better there are no spaces! so it looks great!! i wouldnt worry too much, you've done a such great job providing detail, the pictures are just a bonus!
the reference list looks great! thanks for your help! xox Elide

--[[User:Z3254857|Begum Sonmez]] 20:55, 11 October 2009 (EST)Hello girls! One more thing left: Current Research section. One student said to reduce the number of 'research', but include more information on each. I don't think adding more info under the research is necessary. But '''just keeping the 'breakthroughs'''' would be good, the more important ones. What do you all think? Also, '''what should the headings be''', any suggestion? Should I keep the Organisations as the headings, or the names of the researchers involoved, and/or the dates?

--[[User:Z3224449|Elide Newton]] 11:41, 12 October 2009 (EST) hey. about the current research section. well now that it doesnt have as many spaces and gaps it doesnt look as long, so maybe thats why the student saids to reduce the number of examples. so i'm with you begum, keep the important ones. for example if there are 2 examples of its use in cancer then have only one cancer example. yes headings . i think maybe keep the organisation and date. see what the other girls think.. i'll have a think about it too, and see what we can improve on that section.. overall are we all happy with how its looking? i think its looking great! even the reference list doesnt look messy! :)

--[[User:Z3224449|Elide Newton]] 14:48, 13 October 2009 (EST) Begum! your work is amazing! the current research section looks so much better! I think the page is starting to come together now! what i plan on doing is giving the whole thing a good proof read to make sure the flow, format, text, and info is consistent throughout. what else should we do with it. is everyone liking the improvments so far? dont forget we only have tomorrow to work on it!

--[[User:Z3254857|Begum Sonmez]] 19:43, 13 October 2009 (EST)
Thanks Elide!! I have and will continue proof reading the history and current research section (for any mistakes and grammar issues), so you don't need to proof read those sections in-depth (save you time). Just to let you all know, I may or may not get rid of some current research findings. I think we all did a great job, and our page looks very organised and professional. Well done to all of us.

--[[User:Z3252231|Angama Yaquobi]] 23:14, 13 October 2009 (EST) Hi Girls, as you might have noticed that I have changed some of the images in genetics section and have included more information about each of the images along the source info. I have read and viewed the History section and Current Research, it looks very nice in terms of formatting with alot of improvement, so i am really happy Begum you have done a great job, well done! Eldie I have added few images but am still not sure about one or two images if it has given permission for its use for general public. If i see you on thursday before the start of the lab i will show it to u so that you know what i mean. Like it doesnt say anything about the image that it cant be copied unlike some other websites tht at the bottom of the page it gives u a brief detail regarding the copyright policy. So may be i will tell you on thursday during the Visceral lab. :-) I have also added some terms in the glossary list and I think our page looks amazing. Lets hope that Mark like it. Everyone's section in my perspective looks very interesting and informative. So well done everyone.

--[[User:Z3224449|Elide Newton]] 17:21, 14 October 2009 (EST) '''TO ANGAMA:''' so i had a look at your images in the genetics section. i took the link to the webpage where you got them from to look for copyright laws. unfortunately i couldnt find anything on copyright for all of your images. and without copyright approval they cant be published on our page. so this isnt so good. for the 2 images 'transgenic mouse pup' and 'Conditional Gene Expression' these could possibly get approval from the author Wes Thompson by possibly emailing '''resler@mail.utexas.edu''' . The only thing is the lack of time we have left. the image of the researcher in the current research section doesnt have copyright either, so we might have to get rid of this completely, at least its only showing people and isnt vital to the understanding.

*The image 'Examples of some commonly used mouse strains' has no info describing the point of the picture or source or copyright. does anyone know info about this image, otherwise it shouldnt be on the page.
*The Image of Transgenic Mouse also doesnt have copyright approval.

We just need to fix these few things. so girls if we cant get copyright laws for the images do you all agree we need to remove the images? this is so unfortunate because they are such great images!! :(

overall i'm very happy with our page. I think we have all worked very hard on this assignment and thats all we can do. I'll go over it one more time, but i'm happy with it as it is. thanks all so much for all your effort and work put into this assignment. it has been a pleasure working with you all! please reply asap,so we can fix the images... coz its due in the morning!!!

Hey girls, the page looks much better especially now that the gaps have gone and the contents is much shorter. You've all done lots of work editing the page and it looks as though all your hard work has paid off. sorry that i have not done much editing. Based on the comments that we recieved there wasn't that much that i had to change for my timeline. --[[User:Z3252340|Emily Wong]] 18:48, 14 October 2009 (EST)

--[[User:Z3252231|Angama Yaquobi]] 23:03, 14 October 2009 (EST)
Hi girls, I have removed 2 images since it did not had any information about its copyright though i have added another one along the copyright info. I think that i do not need to add any more images for the genetics section because i think its enough and even though there are so many beautiful images out there in websites but unfortunately got no permission for use. So i think we all have worked very hard for this project and it was a pleasure and fun to work with all u girls. Gud luck girls with exams coming in 2 weeks time.

== List of things still to do ==
* proof read the whole thing
* check if your images have info underneath, reference and copyright liscence (Angama you might need to check your genetics pictures.) If your busy I can do them for you but i need to know the reference and copyright permission. Elide

== Changes made ==
--[[User:Z3224449|Elide Newton]] 12:17, 2 October 2009 (EST)
*Removed table of stages from discussion page
*Corrected introduction " the mouse has a similar genome to the human"
*In stages section changed size of images to 200px and moved to the right
*Removed spaces and gaps from stages
*Formated stages section to look neater
*Deleted the links to tables on discussion page
*Added in table of theiler stages 12-14 which was on the discussion page
*Started a glossary of terms
--[[User:Z3224449|Elide Newton]] 16:17, 5 October 2009 (EST)
*Added in text citations to the staging section
*Added in more definitions for glossary of terms and referenced glossary
*Went through each reference of reference list and changed the format it into APA, bold for incomplete references.. to note that it needs to be fixed.

--[[User:Z3252340|Emily Wong]] 11:28, 6 October 2009 (EST)
* Edited the contents so that it wasn't as long i.e. took out all the repeated "what did he do?" etcs.
* Edited current research so that contents are not as long. Again taking out the "what did the do" etcs.
--[[User:Z3252340|Emily Wong]] 15:38, 8 October 2009 (EST)
* Edited the timeline of development section by:
** Taking out the written text and incorporated it into the captions below each drawing.
** Rearranging the work so that it was in a better position
** Linked the graph 'Average length of the mouse embryo' into the section by writing a small blurb on it.

--[[User:Z3224449|Elide Newton]] 10:44, 9 October 2009 (EST)
* Removed spaces in sections current research and genetics
* Moved images to the right and changed size to 200px in current research section
* re-uploaded theiler stage 8 image with typo fixed ( reichards to Reicherts)
* added information below images in the staging section.
* added links to source below images in staging section
* deleted 'Photo of mouse vascular development at Theiler stage 20' because I am unable to find copyright liscence
* went through each ref and chagned to APA, had to look up dates and authors for incomplete references added by other students. still some are not complete (in bold) so if you added these references could you please fix.

--[[User:Z3254857|Begum Sonmez]] 12:28, 9 October 2009 (EST)
*Changed the heading 'Chromosome number and banding patterns' under Genetics, from being a main heading to a sub-heading. This was a small mistake that had to be fixed.
*Changed the sub-headings of the history section, that list the years, to bolded text. The reason for this change is that it condensed the amount of headings in the 'Contents', allowing the viewer to have an outline of the page instead of a massive list of each heading. As a result, the page looks more neat, and each section is consistent with eachother.
*Placed all pictures in the History section to the right-side of the page. This is more consistent with the rest of the page, and adds to the flow of the page.
*Placed 2 spaces between each finding, and 1 space between each part of the finding (For example, 'What did they find', 'The Importance'). Again, this is another feature which adds to the consistancy of the page. Many of our peers pointed out that our page was messy. This change helps to solve the problem.

--[[User:Z3224449|Elide Newton]] 20:38, 9 October 2009 (EST)
*Removed headings from current research section and made them bold.
*Finished the glossary of terms from the staging section
*worked on current research. (removed spaces, formated, removed lists of names and added 'et al')

--[[User:Z3254857|Begum Sonmez]] 14:45, 10 October 2009 (EST)
*Changed the sub-headings under the Genetics section to bolded text. There were no complaints about this from our peers. However, since this was applied to the History section, applying it to the Genetics section would be consistent and more neat.
*Placed all HISTORY pictures beneath one another in order to be consistent with the arrangement of other pictures throughout the page.
*Deleted some of the headings (what did they, how did they...) under the history section, as the contents of some of the headings were related. One student mentioned this. As a result, there is less headings, and a greater degree of clarity.
*Edited the Reference list by dividing it into 2 headings ('Books and Articles' and 'Webpage'), and converted some more references into APA style. Just one more conversion left.
*Added the definitions of 'Allophenic', 'Chimera', 'Corpus luteum', 'Somatic tissue' and 'Stem Cell' to the Glossary List.

--[[User:Z3224449|Elide Newton]] 19:44, 10 October 2009 (EST)
*Removed headings from staging section and made bold instead to be the same as the whole page
*Removed two gaps from the genetics section

--[[User:Z3254857|Begum Sonmez]] 14:24, 12 October 2009 (EST)
*Changed some of the Sub-headings under the Current Research section to make it more consistent throughout this section.
*Converted the information under each finding under the Current Research section into numerous small paragraphs because one student outlined that the use of the sub-sub-headings were good at first, but it than became overwhelming. This change enhanced the layout without using the sub-sub-headings and without ending up with a slab of text.

--[[User:Z3254857|Begum Sonmez]] 11:18, 13 October 2009 (EST)
*Changes the heading 'THE MOUSE' from all upper-case to lower-case. This is consistent with the other main headings.

--[[User:Z3252231|Angama Yaquobi]] 19:35, 13 October 2009 (EST)
*Removed some of the images in the genetics section because there was not much information about the image.
*Replaced those images with new images containing information about the image.
*Added the definition of 'Haploid', 'Mutation', 'Oncogenic', 'Renaturation', 'Telocentric', 'Transgenic', and 'Transposition'.

--[[User:Z3254857|Begum Sonmez]] 20:20, 13 October 2009 (EST)
*Changed the word 'Are' to 'Is' under the introduction. Just a slight grammatical mistake.
*Added to the comment under the Gregor Mendel picture under the history section, the words 'Copyright has expired'. This informs the reader/viewer about the copyright information. Proof read the Current Research section. Changed a few grammatical mistakes, and deleted unnecessary sentences. This shortened the content of each finding, providing a summary of the key points for the audience.
*Added the reference of images used under the History and Current research section into the reference list. I think this was not done by mistake.

--[[User:Z3224449|Elide Newton]] 21:10, 13 October 2009 (EST)
* proof read. added in 2 sentences to make the transition from 'history of use' and 'stages' flow.
* added a sentence in after the genetics heading to keep the flow on from the last section.
* added in Mb to The haploid genome is about 3 billion '''Mb''' long.
* changed 'tha' the 'the' in genetics section.

--[[User:Z3224449|Elide Newton]] 17:57, 14 October 2009 (EST)
* in looking for images for the genetics section which had copyright laws I noticed the 1st paragraph of the genetics section was the exact copy from wikipedia, so i rephrased the information so it isnt plagarised

--[[User:Z3252340|Emily Wong]] 19:05, 14 October 2009 (EST)
* Resized the images in the timeline gallery so that they were 175px instead of 100px. This made the images have more of a presence on the page.
* Checked spelling and grammar
* linked the timeline section with the staging section by mentioning how long the stages took.
* Put day numbers in bold so that the stand out from the text

--[[User:Z3252231|Angama Yaquobi]] 22:54, 14 October 2009 (EST)
* Proof read the genetics section.
* Removed 2 images because they did not had any copyright information.
* Added a new image "Knockout Mouse". Added information about the image and also have added the copyright information.

--[[User:Z3254857|Begum Sonmez]] 08:22, 15 October 2009 (EST)
*Removed the pictures of 'Whesley Whitten', 'Anne McLaren', 'Beatrice Mintz', 'Teruhiko', and 'Leroy Stevens', as well as 'NIDCR'under Current Research due to unavailability of Copyright information.
*Replaced the pictures with links to the websites containing those pictures.

2009 Group Project 4

2009-10-14T21:19:35Z

Z3254857: /* History of the use of the Mouse Embryo Model */

== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Is a small organism which can be easily maintained
*Is not expensive
----

===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

The mouse model has been used significantly in past scientific experiments. The mouse has many beneficial qualities which allow it to be easily manipulate and studied. One example includes its ability to reproduce and embryological development.

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Fingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development, so far, a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development click the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm. The 26 Theiler stages are covered within 18 days, while stages 27 and 28 are covered during day 19 and the days after birth.
{{Insert timeline}}
----

===Genetics===
[[image:800px-Knockout_Mice5006-300.jpg|thumb|300px|right|Knockout Mice]]
The mouse is extensively used in experimental models because of its genome and its ability to be manipulated and studied.

'''Genome'''

In late 2002 the sequencing of the mouse genome was completed. Scientists have discovered that the haploid genome for the mouse is about 3 billion bases long having a total of 3000 Mb distributed over 20 chromosomes. The size of the mouse genome is closely related to the human genome size. Scientists estimate the gene count of the mouse genome to be 23,786 genes when compared to humans having 23,686 genes, a degree of size similarity can be shown.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino.
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).
[[image:Nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome. Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.

Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function. However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.

[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve in mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===
[[image:NIDCR.jpg|thumb|200px|right|Members of NIDCR]]

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:

1.Supports the multiplication of the H9 cells better than the 3T3 line.

2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1/ An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155), and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on normal hematopoietic stem cells (HSCs).

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy remains uncertain until clinical trials are undertaken in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia et al. used the knockout mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knockout mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cellular differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please click [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| here] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. found that the epithelial-mesenchymal interactions in the development of the Wolffian duct and testis cord are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins, when mutated, become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin ,rather than the bacterial cell numbers, is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents, BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab, on the mice containing EGFR mutated lung tumors. It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''', which has been studied to assist in generating antibody and CD4 T helper cell responses. This process was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Haploid:''' A set of chromosomes containing only one member of each chromosome pair. The sperm and egg are haploid.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Mutation:''' is a randomly derived change to the nucleotide sequence of the genetic material of an organism.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Oncogenic:''' An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Renaturation:''' The process by which proteins or complementary strands of nucleic acids reform their native conformations.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Telocentric:''' a chromosome like a straight rod with the centromere in terminal position.

'''Transgenic:'''A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered using genetic engineering techniques.

'''Transposition:''' is a kind of mutation in which a chromosomal segment is transfered to a new position on the same or another chromosome.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Shiro, I., Meytha, M., Cristina, V., Karen, E., Walid, K., Howard, G. (2006). An immortalized drug-resistant cell line established from 12-13-day mouse embryos for the propagation of human embryonic stem cells. ''Differentiation''. Accessed from http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KJLDc4JX2vKFKSQbLw7SSJTx2pGy4dMvGQJ9zpGxDdZ5hN1YyC6H!-2135654213!181195629!8091!-1

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*Geneall. ''Dame Anne Laura Dorinthea McLaren'', retrieved September 21, 2009. http://www.geneall.net/U/per_page.php?id=557208

*Harvard University. ''Howard Green, M.D.'', retrieved September 24, 2009. http://cellbio.med.harvard.edu/faculty/green/index.html

*Institute of Medical Biology. ''Davor Solter'', retrieved October 12, 2009. http://www.imb.a-star.edu.sg/Default.aspx?tabid=224

*International Knockout Mouse Consortium. ''About the International Knockout Mouse Consortium'', retrieved September 19, 2009.

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Memorial University. ''Oration honouring Wesley Whitten'', retrieved September 11, 2009. http://www.mun.ca/marcomm/gazette/2000-2001/june14/convocation8.html

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*National Institute of Health Record. ''NIDCR Team Creates Mouse Model of Disease'', retrieved September 19, 2009. http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*University of Iowa : College of Liberal Arts and Sciences. ''Alumni Fellows'', retrieved September 26, 2009. http://images.google.com.au/imgres?imgurl=http://www.clas.uiowa.edu/_includes/images/alumni/beatrice.jpg&imgrefurl=http://www.clas.uiowa.edu/alumni/programs/fellows/2002/&usg=__ZTVwhRDWmWlpQWiTgm7QPANk0ow=&h=218&w=182&sz=10&hl=en&start=2&sig2=WxT11tEDMuSTsbeT1PzXjQ&um=1&tbnid=7WxPUu34U_wdOM:&tbnh=107&tbnw=89&prev=/images%3Fq%3Dbeatrice%2Bmintz%26hl%3Den%26sa%3DN%26um%3D1&ei=ECy2Sp_JKMiGkAX9k9XBCw

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

*Wikipedia. ''Gregor Mendel'', retrieved September 20, 2009. http://en.wikipedia.org/wiki/File:Gregor_Mendel.png

*Wikipedia. ''Rudolf Jaenisch'', retrieved September 17, 2009. http://en.wikipedia.org/wiki/File:Jaenisch_2003_by_Sam_Ogden.jpg

{{Template:Projects09}}
[[Category:Mouse]]

2009 Group Project 4

2009-10-13T10:19:38Z

Z3254857: /* References */

== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Is a small organism which can be easily maintained
*Is not expensive
----

===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:Wesley_Whitten.jpg|thumb|200px|right|Wesley K. Whitten]]
[[image:Dame_Anne_Laura_Dorinthea_McLaren.jpg|thumb|200px|right|Dame Anne Laura Dorinthea McLaren]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Beatrice_Mintz.jpg|thumb|200px|right|Beatrice Mintz]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]
[[image:Teruhiko_Wakayama.jpg|thumb|200px|right|Teruhiko Wakayama]]
[[image:Leroy_Stevens.jpg|thumb|200px|right|Leroy Stevens]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

The mouse model has been used significantly in past scientific experiments. The mouse has many beneficial qualities which allow it to be easily manipulate and studied. One example includes its ability to reproduce and embryological development.

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Fingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development, so far, a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development clink the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm.
{{Insert timeline}}
----
===Genetics===
[[image:2greenpupm.jpg|thumb|300px|right|Transgenic mouse pup]]

'''Genome'''

Sequencing of the mouse genome was completed in late 2002. Tha haploid genome is about 3 billion long (3000 Mb distributed over 20 chromosomes) and therefore equal to the size of the human genome. The current estimated gene count is 23,786 and humans are estimated to have 23,686 genes.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino.
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).
[[image:Nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome. Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.
[[image:5chris6m.jpg|thumb|300px|right|Conditional Gene Expression]]
Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function. However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

[[image:Figure3-3.jpg‎|thumb|200px|right|Examples of some commonly used mouse strains]]
[[image:Transgenicmouse.jpg|thumb|200px|right|Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition]]
Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]
[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve in mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===
[[image:NIDCR.jpg|thumb|200px|right|Members of NIDCR]]

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:

1.Supports the multiplication of the H9 cells better than the 3T3 line.

2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1/ An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155), and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on normal hematopoietic stem cells (HSCs).

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy remains uncertain until clinical trials are undertaken in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia et al. used the knockout mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knockout mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cellular differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please click [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| here] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. found that the epithelial-mesenchymal interactions in the development of the Wolffian duct and testis cord are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins, when mutated, become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin ,rather than the bacterial cell numbers, is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents, BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab, on the mice containing EGFR mutated lung tumors. It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''', which has been studied to assist in generating antibody and CD4 T helper cell responses. This process was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Haploid:''' A set of chromosomes containing only one member of each chromosome pair. The sperm and egg are haploid.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Mutation:''' is a randomly derived change to the nucleotide sequence of the genetic material of an organism.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Oncogenic:''' An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Renaturation:''' The process by which proteins or complementary strands of nucleic acids reform their native conformations.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Telocentric:''' a chromosome like a straight rod with the centromere in terminal position.

'''Transgenic:'''A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered using genetic engineering techniques.

'''Transposition:''' is a kind of mutation in which a chromosomal segment is transfered to a new position on the same or another chromosome.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Shiro, I., Meytha, M., Cristina, V., Karen, E., Walid, K., Howard, G. (2006). An immortalized drug-resistant cell line established from 12-13-day mouse embryos for the propagation of human embryonic stem cells. ''Differentiation''. Accessed from http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KJLDc4JX2vKFKSQbLw7SSJTx2pGy4dMvGQJ9zpGxDdZ5hN1YyC6H!-2135654213!181195629!8091!-1

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*Geneall. ''Dame Anne Laura Dorinthea McLaren'', retrieved September 21, 2009. http://www.geneall.net/U/per_page.php?id=557208

*Harvard University. ''Howard Green, M.D.'', retrieved September 24, 2009. http://cellbio.med.harvard.edu/faculty/green/index.html

*Institute of Medical Biology. ''Davor Solter'', retrieved October 12, 2009. http://www.imb.a-star.edu.sg/Default.aspx?tabid=224

*International Knockout Mouse Consortium. ''About the International Knockout Mouse Consortium'', retrieved September 19, 2009.

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Memorial University. ''Oration honouring Wesley Whitten'', retrieved September 11, 2009. http://www.mun.ca/marcomm/gazette/2000-2001/june14/convocation8.html

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*National Institute of Health Record. ''NIDCR Team Creates Mouse Model of Disease'', retrieved September 19, 2009. http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*University of Iowa : College of Liberal Arts and Sciences. ''Alumni Fellows'', retrieved September 26, 2009. http://images.google.com.au/imgres?imgurl=http://www.clas.uiowa.edu/_includes/images/alumni/beatrice.jpg&imgrefurl=http://www.clas.uiowa.edu/alumni/programs/fellows/2002/&usg=__ZTVwhRDWmWlpQWiTgm7QPANk0ow=&h=218&w=182&sz=10&hl=en&start=2&sig2=WxT11tEDMuSTsbeT1PzXjQ&um=1&tbnid=7WxPUu34U_wdOM:&tbnh=107&tbnw=89&prev=/images%3Fq%3Dbeatrice%2Bmintz%26hl%3Den%26sa%3DN%26um%3D1&ei=ECy2Sp_JKMiGkAX9k9XBCw

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

*Wikipedia. ''Gregor Mendel'', retrieved September 20, 2009. http://en.wikipedia.org/wiki/File:Gregor_Mendel.png

*Wikipedia. ''Rudolf Jaenisch'', retrieved September 17, 2009. http://en.wikipedia.org/wiki/File:Jaenisch_2003_by_Sam_Ogden.jpg

{{Template:Projects09}}
[[Category:Mouse]]

Talk:2009 Group Project 4

2009-10-13T10:15:00Z

Z3254857: /* Changes made */

== Project Updates ==
--[[User:Z3283499|Antonio Lee]] 10:57, 2 October 2009 (EST) Hi everyone, I will be working with you during the Lab10 Tutorial and here is the news link and PDF of the manuscript for your group exercise. I encourage you to read the paper before the tutorial. Also, please indicate next to the questions below (using either your initials or student number) which one of the four questions you wish to address.
:'''Group 4 :''' [http://www.scientificamerican.com/article.cfm?id=stem-cells-from-fat-cells '''Induced Pluripotent Stem Cells Created from Fat Cells'''] in Scientific American Published online 8 September 2009 [[Media:ANAT2341_Lab10_2009_Group 4 Reading.pdf|Manuscript (PDF): Feeder-free derivation of induced pluripotent stem cells from adult human adipose stem cells]]

:Question 1. What is the background to the existing problem / disease condition?--[[User:Z3252340|Emily Wong]] 13:41, 8 October 2009 (EST)
:Question 2. What approach / method did the research team take to tackle / improve the problem? --[[User:Z3252231|Angama Yaquobi]] 19:27, 7 October 2009 (EST)(Angama Yaquobi)
:Question 3. What was the breakthrough / major advancement OR failure / drawback? and why might this be of significance?--[[User:Z3224449|Elide Newton]] 13:43, 8 October 2009 (EST)
:Question 4. What are the next steps in moving forward? What are the next or new hurdles to overcome?--[[User:Z3254857|Begum Sonmez]] 12:42, 8 October 2009 (EST)

==Constructive Criticism of Coordinator==
--[[User:S8600021|Mark Hill]] 08:07, 8 October 2009 (EST) The following comments are general in nature in no specific order, as it would be inappropriate to suggest specific changes and then assess the final project. Comments will be added during this week and you still have one week before final submission.

* The project has improved in content and layout from the original submission date.
* A general comment about images. When you click an image and it opens, the information below the image should have an explanation of what the image shows, a reference (if from a paper) and a link to the original source (if available) as well as copyright information.
* There are still issues related to page design with large white spaces visible.
* [[:File:Mice_expressing_GFP.jpg]] What is the original source of this image? Do you have permission to reuse?
* [[:File:Genetics of laboratory rodents.jpg]] What is this transgenic mouse expression pattern showing?
* The Theiler images of embryo stages are useful to have, are they really all redrawn? I will be comparing these to the original online versions and they cannot be direct copies without permission.
* [[:File:Mouse_theiler_stage8.JPG]] Reichard's menbrane?
* Glossary still incomplete.
* Reference could be tidied up.

==Constructive Criticism of Peers==

--[[User:Z3218657|Sally Clarke]] 09:59, 1 October 2009 (EST)Well Done!

I'm just jumping straight into it..

- I Think the timeline stage is fantastic - the images and information are displayed really well

- the staging information is a little cramped and thrown in together - it doesn't flow very well and the images are all over the shop

- The history section has A LOT of information an images of the scientists, what they did and how they did it - great... i know this would have taken a lot of work but its a bit long. I think maybe making it into a timeline on different pages might help this.

- The headings and sub headings are really good and informative but there is a few formatting errors which is easy to fix

- The genetics sections is really good, nice and concise yet informative

Great assignment guys!

--[[User:Z3258567|Sando Rashed]] 09:12, 1 October 2009 (EST)hey wow lots of information in this page :D, well done with the effort use all put in it looks and sounds goood, few things im not sure if it was my computer but staging of embryonic development there was just a bunch of photos and they were crammed up and overlapping each other making it very hard to read use might want to cut down on the photos in that area or scale them down to make it easier to read. you have a lot of information in your history section its good that you have what they do and their contribution to make it look a bit better you might want to split it up into a 3 way table (name/what they do/how it helped) minimise the reading as i recall dr mark saying to much reading is not something he wants he wants something more appealing to him where he can lay in bed and mark it without falling asleep so a table would be good here. other than that its a great page :D well done hope use all do well!!

--[[User:Z3223194|Bronwyn Lewis-Jones]] 08:53, 1 October 2009 (EST) Congratulations on a great assignment. There are so many good things about this page. I think the biggest (and easiest) improvement to be made is to cut down on the amount of headings for the History and Current Research. The headings used such as "What did they do?" etc are helpful in showing the reader what exactly they are to understand from what is written, however they interrupt the flow and spread out the information so that it seems rather daunting. If you can summarise each section into a few sentences then I think that will not only reduce your contents section to a more useful size but also make the page more reader friendly. If you don't like that idea you could strike a happy medium by either having you "What did they do..." to bold instead of a heading or have (in bold or italics) a very short summary sentence under the name followed by a short few sentences. This would still give the reader an impression of what do get out of each section but would increase the flow inside and between notable researchers etc. Hope you find this helpful. :)

--[[User:Z3218146|Julianna Lam]] 01:31, 1 October 2009 (EST)
- the history section is TOO long ! the structure of the history section is good, i liked the whole idea of the sub headings ie ' what did he do?' but i think you guys included way too many people in there. the layout of the history section is not very neat and very inconsistent. you provided pictures of some people but didnt provide pictures of others. there are gaps everywhere and it just looks really messy.

- the stages and timeline parts are really good. the table looks really nice. and i especially like the pictures, very well labelled.

--[[User:Z3186093|Jenny Guy]] 18:46, 30 September 2009 (EST)

Improvements:
* The history is wayyyy too long. Seriously, there are too many sub sub sub headings. Cut it down and for each scientist make it a paragraph instead of so many dot points. I almost couldnt be bothered reading them all. Definitely not a good way to represent information. Looks as though you gave up on looking for pictures of the scientists. I would too if i had that many of them. Pick the main scientists that caused a breakthrough instead of listing all 1000 of them. Also, it is inconsistent if you did decide to keep the subsubsubsub headings as 'what he did', "what he found" and "what the importance" are generally all targeting the same question.
* I think you guys are confused as your information is conflicting. Humans have 23 pairs of chromosomes. In your introduction you state they humans and mice have the same number. However in the genetics it states that mice have 20pairs. What is true?
* There are a few gaps (large random spaces) in the genetics sections. Might want to format this a little.
* For the current research see the same massive point i mentioned first....
* Your referencing in the bibliography is inconsistent. Stick with one type of system, e.g. apa OR harvard. Some of the references aren't even referenced properly. You must reference websites.
* You haven't referenced ANY of you text. How do we know you havent just cut and paste? You need to either reference within the text (e.g. Andrews, E.A. (1895) states .....) or at the end of sentences/paragraphs with (Andrews 1895) or the number used in the bibliography.

--[[User:Z3255007|Sadaf Masood]] 15:43, 30 September 2009 (EST)Hey Group 4! Congrats on your great project guys! I have listed few points that might help:

1. Very well researched History section, lots of people doin lots of work..maybe you can make it a little short as its just a little too much info on them.

2. A bit more proper formatting, lots of gaps after every picture and table, maybe you can get rid of them

3. Timeline is great, just enough info to make sense and needed.

4. 'Why use of mouse is important?' this issue is well discussed. Great work!

5. Impressive hand drawn diagrams, any chances of making them a little larger on the main page? it would look really good!

6. Glossary is also needed...will make our life easier is understanding few words.

Rest is all well guys. The current research Section is awesome, very informative and lots of details. Its a great project guys...Best of Luck!!

--[[User:Z3218792|Gabriela Pinget]] 12:59, 30 September 2009 (EST) Hello! constructive criticism as follows:

- intro is a nice ease in but needs to be edited for grammar

- wow the history section is very well researched. I like that you've included so many contributors but are you sure you need to go into so much detail? It looks a little cluttered and detracts from the overall purpose of the assignment. Think about cutting down on it a little

- I really like the ''staging of embryonic development'' section! very engaging and well formatted! well done

-I also liked the timeline of development. I like that there was not too much information at each stage, but just enough to give a clear outline. Maybe a link to find out more would be useful

- genetics section is perfect

- again, the current research section is a little too spread out. The continuous "what did they do..." works well to begin with but after a while gets to be too much

Overall, a really nice looking page

--[[User:Z3295026|Joe Nassif]] 17:59, 29 September 2009 (EST)

Awesome looking wiki page, mouse group 4 an excellent assignment.

It is a really interesting reading and viewing your wiki page the content flow really well when reviewed.

1. The assignment is impressive it outlines the point with the use of sub headings which is always useful in the project as a referencing point.

2. (What did he do?) and (What did they find?) is a great way to state the history as it allows the reader to quickly get the brief information and understand it , also the illustrations throughout the assessment was great it referred to the text really well, which supported the info impressively. The hand drawn images in the (staging) and (timeline) sections were extremely great the detail was impressive.

3. Some ways to improve the assignment:
A) There are some unnecessary data throughout the project which are not relevant for example the ‘length of mouse embryo’ , removing this sections can truncate the assignment which would enhance the structure.

B) Current research information on the background of the research finders reveal great info on the development of the model usage, the findings and the relevance to human embryology have been summarized greatly.

C) The referencing need to be fixed in proper format. Visit : www.lc.unsw.edu.au/onlib/ref_apa.html for help with APA referencing

D) a glossary is needed to help the reader understand terms.

Overall a great project. The criteria was covered really well it, stated specfic topic in regards to the mouse and it embryonic developent which group 4 has summarised really well.

--[[User:Z3295026|Joe Nassif]] 17:59, 29 September 2009 (EST)

--[[User:Z3217015|Mitchell Mathieson]] 09:39, 25 September 2009 (EST)Page looks good. I liked how there was heaps of information on the genetics and the current research (however, this was a bit too spread out maybe). There seems to be a lot of gaps in the text, so the formatting could be maybe tightened up. The references maybe should be formatted better, and there is repeated information (tables and text for stages), but I really like how clicking the image goes to another page with more information...that is cool. The drawings are cute as well. Overall very good, I think formatting was the downfall from that, but the information is top notch.

--[[User:Z3126328|Jin Lee]] 16:42, 26 September 2009 (EST) hellow group4~ very impressive assignment guys!well done! I really enjoyed reading your assignment. it was easy to read and the information was relevant. However, I found the formatting of the images and texts were too sqeezy. may be resize the images and line up with the relevant information. Also, I think the reference needs to be looked after as well. Overall, the contents of the assignment is very useful and interesting.

--[[User:Z3187802|Vishnnu Shanmugam]] 20:02, 26 September 2009 (EST)Congratulations mouse group on an excellent assignment. It is a real joy to read. One of the best features of the assignment is how it gets straight to the point with the use of sub headings “What did he do?” & “What did they find?”. Even the images used throughout the text are interesting, especially the fully labeled hand drawn images in the “staging” and “timeline” sections. Some ways to improve the assignment:

-There are some unnecessary graphs in the assignment such as “the average length of mouse embryo”, “number of cells” and “number of somites”. These could perhaps be combined into a single graph. It will also reduce the congested appearance of the assignment as it seems too densely packed with no particular focus.

- In current research section, it is advisable to reduce the number of research and focus on just a few but provide more comprehensive information on the background of the research, the findings and the relevance to human embryology. It currently contains too many different types of research that have described very briefly.

- Edit the "content" section at the top of the page as it's length seems to be getting out of control. It is perhaps better to exclude the sub headings “What did he do?” & “What did they find?” in the contents.

- The referencing in the text need to be completed as there are some sections well referenced and others with no referencing. see www.lc.unsw.edu.au/onlib/ref_apa.html for help with APA referencing

- A Glossary would also complement the text.

Overall a classy project, only some changes necessary

--[[User:Z3126345|Gang Liu]] 16:49, 27 September 2009 (EST)This is one of the better wikipage i have seen so far. It demonstrates not only extended literature research skill, but also an in-depth understanding of the topic. The content of this page has been consistent throughout. In addition, paragraphs are straigtforward and concise, and make the point. Detailed texts with accessory graphics are appropriate in here. In paticular, history section. It describes the model use in terms of details of experiment, and results of experiment. Stages and timeline are very self-explanatory and visually enhanced.

This project can be improved by considering the following points.

*Lack of glossary list. Need to provide meaning of words such as "polyestrous", "oocyte", "Ectoderm", "endoderm", etc;

*Reformat stages section. I found this section a bit "busy". Might considering resize the pictures.

Last few words. I have learnt from this page that mouse has the same size genome as the human genome; Mouse genes can be easily manipulated and studied; Mouse a high degree of homogeny with humans. Well done!

--[[User:Z3217686|Thomas Dangerfield]] 14:12, 28 September 2009 (EST)Hey guys! Wow so much info first off! Not entirely sure we need to know about everyone involved in the history, maybe could have collaborated and joined people together or possibly even left certain people out. To me, the whole page is like how mark described, with everything all one great smudge of info with no real formatting or sequence or continuation. It was just kind of like an overload and reading it was a little difficult at some stages. Also corresponding the images in the timeline could have been included in the text.

Also I think your numbering of figures is a little off in the timeline section, with figures 1-4 on the right and then you have figures 4-7 describing stages 12-14. Just seems that there is two figure 4's for two different images.

Love the large amount of research and information, but could just work on your presentation and you'll do fine! Great work guys!

--[[User:Z3185685|Sumaiya Rahman]] 16:56, 28 September 2009 (EST) Hey guys! Overall a very nice assignment with a great deal of information! You can tell you guys did a lot of research. The contents are massive! Maybe you could cut this down and not use so many subheadings such as “what did they do?”, “what did they find?” and only have a subheading for each researcher. The introduction is well written. The history of model use has some really good information. My only criticism in this section is that there are a lot of gaps and blank spaces. You just need to delete all the spaces. The staging section showed a lot of research and effort. Well done!! The only thing is, is it a bit too much? There are a lot of tables and images that it was hard to keep track. Maybe this could be set out differently and made to look less busy. The timeline of development is fantastic and set out really well. It is very easy to understand and the drawings are great! Once again the current research is very spread out with lots of spaces. Also adding a glossary may help the readers in understanding the text. GREAT JOB!

--[[User:Z3215682|Carly Mooney]] 11:49, 29 September 2009 (EST)
I think all your material is there but the page layout needs work. Especially the history of the models use.
*The spacing and images are inconsistent. I liked the history of timeline section information and how it was presented, just the spacing of it all needs to be even.
*The stages of embryonic development was a little all over the place, and very daunting to look at.
*A glossary would help.
I think you guys did a really good job and just have to work on presentation.

--[[User:Z3220040|Joanne Raffel]] 16:14, 29 September 2009 (EST) Very impressive page, however it was very long!!! The introduction was very clear and concise. The history section was extremely long and poorly formatted, there were too many pictures with too little information, I would recommend cutting some of the images and just keeping the pictures of those who made a significant impact upon the mouse embryo, I also thought it was unneccessary to write after each subheading, what did he do and their result, I would prefer if it was just one paragraph. Your main heading were overshadowed by the subheadings and the rest of the text. There is a lot of information for the staging section, which is good however it can made it difficult to read, I would recommend having some of the information linked onto a separate page. The picture and format for the timeline section was exceptional however it lacked information, I also thought that it was irrelevent rewriting the timeline after the pictures, I would recommend including it with the picture rather than after it and the graph size made it seem insignificant. The genetics section was very extensive and I thought some of the information was better included with the current research. Similar to the history section, I thought the formatting of the current research section was very unorganised and too spaced out. Overall a very nice page.

----

--[[User:S8600021|Mark Hill]] 01:46, 8 September 2009 (EST) Well the content is there now, but what a mess, and I am not just talking about the formatting problem which can be easily fixed, you have no structure to your project, its not a matter of throwing everything at a wall and seeing what sticks. Work together for an integrated coverage. Timeline of development, is not the way to start your page with a huge table of data.

--[[User:S8600021|Mark Hill]] 08:43, 21 August 2009 (EST) OK guys, time to see some actual content uploaded on both your discussion and project pages.

* Timeline of Development - how long (Emily)
* Staging - are there species specific staging, what occurs when (Elide)
* History of Model Use - when was it first used, what embryology research (Begum)
* Genetics - chromosome number, sequencing (Angama)
* Current Embryology Research - research papers and findings (All)

Here is a link for timeline
[http://books.google.com.au/books?id=XLIarRWHikAC&pg=PT199&lpg=PT199&dq=mouse+embryo+development+timeline&source=bl&ots=fobLBRiacx&sig=cK4cuZah6Ksczs3o8v4NXQqoAyk&hl=en&ei=rGB6SvTHMMmIkAXB_piAAw&sa=X&oi=book_result&ct=result&resnum=3#v=onepage&q=&f=false
]

link for the mouse brain development timeline http://en.wikipedia.org/wiki/Mouse_brain_development_timeline

hey guys there is another interesting link about mouse development http://mouseatlas.caltech.edu/index_content.html

Hey Emily. The link below has a timeline that you can check out in your spare time. Begum.
[http://books.google.com.au/books?id=4juoa5xMs8oC&pg=PA31&lpg=PA31&dq=mouse+embryology&source=bl&ots=9tJAfRG4R6&sig=hjR5Zs-sL1sCW5FY8FnR5TMaUk0&hl=en&ei=LuuMSr_aCNjakAX714icDA&sa=X&oi=book_result&ct=result&resnum=9#v=onepage&q=mouse%20embryology&f=false]

Hi girls,
here is a link to a text book about mouse embryology it looks pretty good. hope it can help
[http://books.google.com.au/books?id=4juoa5xMs8oC&printsec=frontcover&dq=mouse+development&source=gbs_similarbooks_r&cad=2#v=onepage&q=mouse%20development&f=false]
let me know if the link doesnt work. Ive been working on the main page, so have a look and tell me what you think, Also what are we doing about references? If we have used information but put it in our own words do we need to put in text citations,or do we just reference the journal at the end? I just want to be very careful. Thanks!

Hey Elide, i think your work is looking really good. its very easy to read and understand. keep going!!!! emily

hey everyone,
I have uploaded some of my timeline work. I'm not sure if I've gone into to much detail or not and also on how is best to present the timeline. It is fairly basic and definately needs some work - especially on presentation, grammar, etc. let me know what you think.
Emily

good site for stages or timeline- atlas of pictures of stages- The Edinburgh Mouse Atlas Project [http://genex.hgu.mrc.ac.uk/]

Hello girls, it's Begum. I put some info under the history section. Wanted to let you all know that I've got a fair bit of info, and I will do my part as best as I can. Btw Emily, I think maybe dot from would be best for you, but if you can use those lines that I was talking to you about on Wednesday, that would be great...I know it's hard.

hey everyone, i have put some info under the genetics heading and some under research. I am still struggling to find the appropriate info related to the topic of genetics because there is alot of info abt the different types of stains used in labarotories but not the genetics. I emailed Dr.Hill and have asked him what to include in my section specifically,hopefully he will help. So far i have just started it needs alot of more work to be done,girls just read thru my section n leme know wt u think of it. have a nice weekend everyone. Angama.

Hi girls!
Begum, you history info is really good. If very interesting! I really like how you are doing it in order of dates of discovery and what they did, what they found etc! Cant wait to know more.
Angama, your doing well! it sounds like your finding the info hard to get. I'll keep an eye out for you! If your stuck on what you sound be doing then i might have a few ideas. I remember Mark Hill saying that you should compare the genome to the humans genome. so maybe if the genome is the same size as the humans, could you descibe similarities or differences? I know that there is a link to the mouse genome on the mouse web page he gave us ( next to the discussion link). Are you just ment to list the mouse genome sequence? could you go into what genes code what, eg which one codes for the sex linked gene, is it the X and Y gene etc? hopefully Mark gives you some ideas.
well as you might have noticed i've been adding to my stages. the only thing is im worried about there being too much info up there. basically ive tried to get all the info available included in my stages to make sure i cover everything, and then later i'll go over it all and edit and polish it up a bit. Ive done some drawings to the best of my ability, but i can scrap them if you all think they arnt professional enough. just thought i'd try to present the information differently. let me know if you think i'm including too much information. i think i'm having the same problem as you begum, there is lots of info! Elide

Thanks Elide. I'm trying. (Again, loved the artwork!)Btw, Emily, I had a think about your section and I think it might be too much 'clicking' back-and-forth if we link the displayed pic to the 'info' page. Don't stress, you've got the info (heaps which is excellent) but make sure you get some pictures soon so we can start drawing (I'm helping with the drawings as well ok). Mark said 'Nature' and 'Science' have useable images so lets make that our start.
BTW, I will be using the question mark symbol(???) so I don't forget to reference. Begum

Hey everyone, I have found an online text book. it has a chapter on genetics and history and a lot of other stuff. [http://books.google.com.au/books?id=Vt6nUmz1yEQC&pg=RA1-PA207&dq=mouse+development+anatomy&client=firefox-a#v=onepage&q=mouse%20development%20anatomy&f=false] Emily

Hey girls. If you've seen my section, the info is not on the main page, but linked to another page. I thought that it might make everything look more neat. I thought we could all do it like that. It's just an idea. Something different. Maybe we could have something on the main page (picture of a mouse). Your thoughts everybody? Begum

hey begum, ur work looks really good. i like the idea of linking the work to another page. - we don't have to worry about to much info being on the front page and it gives people to option of viewing the work if they want to. ive been working on drawings, i'll show them to you next week but am not sure how to upload them at the moment. Emily

Thanks! That sounds great that you like the idea. About the photos that you are drawing, if there by hand, you can scan them somehow. But overall,
1. click 'Upload File' on the left hand side of this page
2. New page comes up: click 'Browse' and choose your file that you want to upload.
3. Name it (under the Browse button)
NOTE: write down what you named the file as because like Elide says "...it's going to be lost in space!..."
4. Write down info/comments (like who is the author (YOU), and if the drawing is based on a picture)
5. UPLOAD!
6. Go to your section and just normally type this down to the area you want the picture to be seen:
[[image:THE NAME THAT YOU SAVED THE FILE UNDER.jpg|thumb|200px|right|WHAT YOU WANT THE FILE NAME TO VISUALLY COME UP AS]]

Your thoughts Angama and Elide? (about the linking of our sections to separate pages?) Begum.

Oh and another thing:
What do you girls think about my page, I've got a heading for each DATE and underneath each there are further subheadings (e.g. 'What did he do?'. Should I change them to just text, I mean, does it look messy with sub-sub-headings? Begum.

wow girls! great work.. okay so i asked mark about a new page and he said to avoid it because our info is meant to be on our one page. he said if there is extra information on what we wanted to say but is too much for the main page then have a link to our discussion page. (which is what im going to do) Begum your new page is fantastic!! you have done lots of work! but why dont you just put it on our main page? also girls i think we are getting too carried away with info. just keep it simple! i'm sorry i havent been around this week to work on it but i plan to get going asap. just fixing up some things, summarising, writing introductions etc.
did you all read his note about slabbing info onto our page?? how about some introductions, and sentences to ease ourselves into the content. planning on trying to work on that now anyway..

also lets get the information flowing. why dont we go intro, history of model use, stages, timeline, genetics, then current use.. what do you all think?

hey, i thing that that sounds like a good, logical way to do the page. i've finished the drawings, just need to upload them. About the timeline information, is there anything specific that i should include. the stuff that is on the page is a little vague and so i need some advice as to what are key points that i should include. i know that the drawing are very simplistic, let me know wjat you think about them. ive put one up below. i just need a way to link it to text. emily

Thanks Elide. You know, I think that's a great idea. Have it all on one page, seems less 'diverging...', seems more COMPLETE. I love the ORDER as well. I'll fix all that up!

Hey girls, please have a look at what i've done on the timeline. the images are all hand drawn based upon the text: 'the house mouse'. if anyone could give me any ideas on how best to present the pictures - which would be better - next to or below the text? keep in mind that it is incomplete and there is an illustration for each day of development (i.e. 19 in total). if you think that is too many let me know, some may be similar to Elide's ones. Also, do you think i should put some colour into the drawings? Emily

I love your work Emily. All you need to do is put the info on the growth of the mouse that is on the main page, onto the page with the graph of the growth of the mouse embryo...we talked about that before any way-AND I think your parts finished! Begum.
Angama, I added something to the end of your section that I thought was interesting. Have a look. And are you mentioning manipulation and 'shut-down' of the genes in your section?? Begum.
To everyone, apparently ''Mus Musculus'' is the scientific name of the common house mouse, not the mouse. I was thinking of editing that.

HEY EVERYONE! well i've added in some pictures just to make it look more visual, change them if you have better ones.. and i'm going to be working on the current research section tommorow. oh i also added some graphs like we thought of for emilys section.. so i think my section is finished finally! what do you think? can i just say, I think the whole thing looks great! you girls have been a pleasure to work with! :) Thanks so much!!

hi girls, i am sorry..i have been very busy during the mid-sem break and i know we all had our exams and assignments due. but i was having some issues in my family and also the exams and assignments so didnt really had the chance to read wat u girls have got on the main page. i just finished reading thru it and it looks amazing..WELL DONE GIRLS!! you all have done a marvellous job...Eldie and Begum thanks for suggesting some main points to add for the genetics.i am currently working on it.. hopefully tonight i will have all the information on the page..Begum i love how you have presented alot of info into a very easy and understandable way..it makes so much sense..n it looks very nice with the pictures. Eldie and Emily great amount of work and the pictures and the graphs are superb. i just had a look to other groups pages. n i think so far our page looks very interesting with concise info n amazing pictures. n Begum yes i read what you have added thanks for tht..i will cu girls around..gudluck everyone. cheers. Angama.

Girls can you please help me out.. i am so annoyed..
like rite now i was typing some info and when i clicked to save.
it says "conflict" so i think some one else is also editing
the page at the same time that i am. and i lost all my work..arghh..
so which means i have to type it all again.
is there any other way that it tells me that someone else
is also using it so i dont click on save or even preview
because when i do tht i lost all the work tht i had.
If anyone knows please let me know. thanks. Angama.

Current research : I have put some information in the current research part. not sure where they should be put. Begum, as discussed you can edit it or place it in its appropriate place.

Don't stress Angama at all, now you know, it will be over soon. Uploading it easy:

1. click 'Upload File' on the left hand side of this page

2. New page comes up: click 'Browse' and choose your file that you want to upload.

3. Name it (under the Browse button) NOTE: write down what you named the file as because like Elide says "...it's going to be lost in space!..."

4. Write down info/comments (like who is the author (YOU), and if the drawing is based on a picture)

5. UPLOAD! 6. Go to your section and just normally type this down to the area you want the picture to be seen:

It's easier than it is typed! Of you still have problems I will be at the embryo lab, of there is exams there the ANAT LAB opposite to it, if not Level 3 library computers.

[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19538749| maternal diabetes alters transcriptional programs in the developing embryo], [http://www.ncbi.nlm.nih.gov/pubmed/19414407?ordinalpos=35&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum|Abnormal mammary gland development in MMTV-CBLC transgenic mouse], [http://www.ncbi.nlm.nih.gov/pubmed/19394325?ordinalpos=40&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum|Sonic hedgehog signalling inhibits palatogenesis and arrests tooth development in a mouse model of the nevoid basal cell carcinoma syndrome.], [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=55&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum| Fibroblast growth factor 18 gives growth and directional cues to airway cartilage.]

Hi girls, i think i have completed my section. could you all please just read thru it and leme know wat you think of it. i did it to the best of my ability. Hopefully you will all like it if you girls think therez anything more to add or to delete leme know..thanks. gudluck girls. Angama.

Angama your work is fantastic! Thanks so much! im sorry i wasnt around to help you with the problems. hope it went okay. your info is perfect! im very happy with our page! lets hope everyone else is :)

I love it Angama, good work! And the pictures you uploaded are very interesting. Cool. Awesome. Your done!! Begum.

Thanks Begum :) Girls gudluck and cu all tomorrow. Angama.

== Discussion after peer assessment and constructive criticism ==

Hi girls,
Ive started making some changes to the page based on the comments recieved.
Note i've also started a glossary of terms. Also many of our comments regarded our references,so It would be great if we could all reference the same, lets say APA because this is the most common way for referencing. I have gone through our references and tried to format them in APA. many are incomplete references so i have bolded the references that are missing detail. please if you all could complete your references that you added to the list. Also shall we number the references so we can include the numbers in the text as in text references? like foot note? what do you all think... there have been many comments on our current research page.. so how would you all like to fix it? I personally think its way too much. It seems to have accumulated heaps of info from when I last saw it. Is there anyway of summarising the current research info to focus more on how they are used rather than the institute and scientists involved. I think the most important info in this section is what mice are being used to discover currently and proof of the year of study. Cant wait to hear what you all think! Elide

one more thing.. ive tried to edit the contents, as one of our peers suggested, however i cant seem to edit it. do any of you know how to do this?
Elide

hey emily, i see you have reduced the heading in the contents!! thats great! i was just thinking that maybe we dont need so many headings in those 2 sections at all. what do you think about just making all the scientists and the names of people/ labs just in bold.?

Hi girls, have a look at the changes i have made to my section. let me know what you think. Emily

looks good!!
also girls could you please add words from your sections to the glossary, as that whole list is only from the staging section. thanks. elide

Hello girls. I will be re-formatting the history section in order to get rid of the 'gaps' that my peers have mentioned. Also, Elide mentioned yesterday that placing all the 'History' pictures towards the right-side of the page would look more neat, as well as add to the flow of the page. I think this is a great idea. Begum. Oh, and '''what do you guys think about taking out some information (findings)?''' Some students have mentioned that there is too much information/researchers.
And Elide, I'm might change the names of the researchers. like you said before, to bolded text. It would look much more neat. I might, also, '''apply this to the Genetics section. What do you all think?'''

'''Begum's Problem'''
Hey. I placed all pictures to the right-hand side (history section), but the pictures don't correspond well with the text. Any suggestions?? Should I than put the towards the left? Love the change to the timeline section Emily.

HEY BEGUM!!
so your problem.. I dont think the pictures need to match up because if they have a title of the person then the reader can find their picture. plus the comments are on the spaces and gaps between text, not the pictures.. so maybe just put them all underneath each other and even if they dont match up then at least the writing looks more organised. try making the images 200px and not so large and it could work better?. also the bit about taking out the headings in the genetics would be great!! bold would still look fine! goodluck! xox

--[[User:Z3254857|Begum Sonmez]] 14:54, 10 October 2009 (EST) '''TO ELIDE''': I was going to change the headings 'Reproduction' and 'Theiler Stages' under STAGES to bolded text. What do you think? Plus, like you said before, I'm on that ref. list, I will summarise the current research, and change those headings. If the HISTORY pictures match up to the the text, it would be more convenient for the viewer, don't you all think so??? However, the text would appear better the other way with the images al together on the right. Yes, I'll do that.

Hey '''Begum'''!
yes what a great idea about changing the headings in the staging section! the whole page needs to have the same structure throughout! I shall change them right now! :) i'm a little confused about the bit you said about what you said about the ref list. do you mean that you will fix yours? ive been through some of them and looked up the missing details. some are lacking their full reference though. but that would be so great if you could fix up your references. i think the ones in bold are the ones still needing work, but correct the others if you think they arent finished.
well i think the history section looks great! even though the pictures dont match up, they are still there and they look neat and have the same format as the rest of the page. and even better there are no spaces! so it looks great!! i wouldnt worry too much, you've done a such great job providing detail, the pictures are just a bonus!
the reference list looks great! thanks for your help! xox Elide

--[[User:Z3254857|Begum Sonmez]] 20:55, 11 October 2009 (EST)Hello girls! One more thing left: Current Research section. One student said to reduce the number of 'research', but include more information on each. I don't think adding more info under the research is necessary. But '''just keeping the 'breakthroughs'''' would be good, the more important ones. What do you all think? Also, '''what should the headings be''', any suggestion? Should I keep the Organisations as the headings, or the names of the researchers involoved, and/or the dates?

--[[User:Z3224449|Elide Newton]] 11:41, 12 October 2009 (EST) hey. about the current research section. well now that it doesnt have as many spaces and gaps it doesnt look as long, so maybe thats why the student saids to reduce the number of examples. so i'm with you begum, keep the important ones. for example if there are 2 examples of its use in cancer then have only one cancer example. yes headings . i think maybe keep the organisation and date. see what the other girls think.. i'll have a think about it too, and see what we can improve on that section.. overall are we all happy with how its looking? i think its looking great! even the reference list doesnt look messy! :)

--[[User:Z3224449|Elide Newton]] 14:48, 13 October 2009 (EST) Begum! your work is amazing! the current research section looks so much better! I think the page is starting to come together now! what i plan on doing is giving the whole thing a good proof read to make sure the flow, format, text, and info is consistent throughout. what else should we do with it. is everyone liking the improvments so far? dont forget we only have tomorrow to work on it!

--[[User:Z3254857|Begum Sonmez]] 19:43, 13 October 2009 (EST)
Thanks Elide!! I have and will continue proof reading the history and current research section (for any mistakes and grammar issues), so you don't need to proof read those sections in-depth (save you time). Just to let you all know, I may or may not get rid of some current research findings. I think we all did a great job, and our page looks very organised and professional. Well done to all of us.

== List of things still to do ==
* proof read the whole thing
* check if your images have info underneath, reference and copyright liscence (Angama you might need to check your genetics pictures.) If your busy I can do them for you but i need to know the reference and copyright permission. Elide

== Changes made ==
--[[User:Z3224449|Elide Newton]] 12:17, 2 October 2009 (EST)
*Removed table of stages from discussion page
*Corrected introduction " the mouse has a similar genome to the human"
*In stages section changed size of images to 200px and moved to the right
*Removed spaces and gaps from stages
*Formated stages section to look neater
*Deleted the links to tables on discussion page
*Added in table of theiler stages 12-14 which was on the discussion page
*Started a glossary of terms
--[[User:Z3224449|Elide Newton]] 16:17, 5 October 2009 (EST)
*Added in text citations to the staging section
*Added in more definitions for glossary of terms and referenced glossary
*Went through each reference of reference list and changed the format it into APA, bold for incomplete references.. to note that it needs to be fixed.

--[[User:Z3252340|Emily Wong]] 11:28, 6 October 2009 (EST)
* Edited the contents so that it wasn't as long i.e. took out all the repeated "what did he do?" etcs.
* Edited current research so that contents are not as long. Again taking out the "what did the do" etcs.
--[[User:Z3252340|Emily Wong]] 15:38, 8 October 2009 (EST)
* Edited the timeline of development section by:
** Taking out the written text and incorporated it into the captions below each drawing.
** Rearranging the work so that it was in a better position
** Linked the graph 'Average length of the mouse embryo' into the section by writing a small blurb on it.

--[[User:Z3224449|Elide Newton]] 10:44, 9 October 2009 (EST)
* Removed spaces in sections current research and genetics
* Moved images to the right and changed size to 200px in current research section
* re-uploaded theiler stage 8 image with typo fixed ( reichards to Reicherts)
* added information below images in the staging section.
* added links to source below images in staging section
* deleted 'Photo of mouse vascular development at Theiler stage 20' because I am unable to find copyright liscence
* went through each ref and chagned to APA, had to look up dates and authors for incomplete references added by other students. still some are not complete (in bold) so if you added these references could you please fix.

--[[User:Z3254857|Begum Sonmez]] 12:28, 9 October 2009 (EST)
*Changed the heading 'Chromosome number and banding patterns' under Genetics, from being a main heading to a sub-heading. This was a small mistake that had to be fixed.
*Changed the sub-headings of the history section, that list the years, to bolded text. The reason for this change is that it condensed the amount of headings in the 'Contents', allowing the viewer to have an outline of the page instead of a massive list of each heading. As a result, the page looks more neat, and each section is consistent with eachother.
*Placed all pictures in the History section to the right-side of the page. This is more consistent with the rest of the page, and adds to the flow of the page.
*Placed 2 spaces between each finding, and 1 space between each part of the finding (For example, 'What did they find', 'The Importance'). Again, this is another feature which adds to the consistancy of the page. Many of our peers pointed out that our page was messy. This change helps to solve the problem.

--[[User:Z3224449|Elide Newton]] 20:38, 9 October 2009 (EST)
*Removed headings from current research section and made them bold.
*Finished the glossary of terms from the staging section
*worked on current research. (removed spaces, formated, removed lists of names and added 'et al')

--[[User:Z3254857|Begum Sonmez]] 14:45, 10 October 2009 (EST)
*Changed the sub-headings under the Genetics section to bolded text. There were no complaints about this from our peers. However, since this was applied to the History section, applying it to the Genetics section would be consistent and more neat.
*Placed all HISTORY pictures beneath one another in order to be consistent with the arrangement of other pictures throughout the page.
*Deleted some of the headings (what did they, how did they...) under the history section, as the contents of some of the headings were related. One student mentioned this. As a result, there is less headings, and a greater degree of clarity.
*Edited the Reference list by dividing it into 2 headings ('Books and Articles' and 'Webpage'), and converted some more references into APA style. Just one more conversion left.
*Added the definitions of 'Allophenic', 'Chimera', 'Corpus luteum', 'Somatic tissue' and 'Stem Cell' to the Glossary List.

--[[User:Z3224449|Elide Newton]] 19:44, 10 October 2009 (EST)
*Removed headings from staging section and made bold instead to be the same as the whole page
*Removed two gaps from the genetics section

--[[User:Z3254857|Begum Sonmez]] 14:24, 12 October 2009 (EST)
*Changed some of the Sub-headings under the Current Research section to make it more consistent throughout this section.
*Converted the information under each finding under the Current Research section into numerous small paragraphs because one student outlined that the use of the sub-sub-headings were good at first, but it than became overwhelming. This change enhanced the layout without using the sub-sub-headings and without ending up with a slab of text.

--[[User:Z3254857|Begum Sonmez]] 11:18, 13 October 2009 (EST)
*Changes the heading 'THE MOUSE' from all upper-case to lower-case. This is consistent with the other main headings.

--[[User:Z3252231|Angama Yaquobi]] 19:35, 13 October 2009 (EST)
*Removed some of the images in the genetics section because there was not much information about the image.
*Replaced those images with new images containing information about the image.
*Added the definition of 'Haploid', 'Mutation', 'Oncogenic', 'Renaturation', 'Telocentric', 'Transgenic', and 'Transposition'.

--[[User:Z3254857|Begum Sonmez]] 20:20, 13 October 2009 (EST)
*Changed the word 'Are' to 'Is' under the introduction. Just a slight grammatical mistake.
*Added to the comment under the Gregor Mendel picture under the history section, the words 'Copyright has expired'. This informs the reader/viewer about the copyright information. Proof read the Current Research section. Changed a few grammatical mistakes, and deleted unnecessary sentences. This shortened the content of each finding, providing a summary of the key points for the audience.
*Added the reference of images used under the History and Current research section into the reference list. I think this was not done by mistake.

--[[User:Z3224449|Elide Newton]] 21:10, 13 October 2009 (EST)
* proof read up untill stages. added in 2 sentences to make the transition from 'history of use' and 'stages' flow.

2009 Group Project 4

2009-10-13T10:05:07Z

Z3254857: /* References */

== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Is a small organism which can be easily maintained
*Is not expensive
----

===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:Wesley_Whitten.jpg|thumb|200px|right|Wesley K. Whitten]]
[[image:Dame_Anne_Laura_Dorinthea_McLaren.jpg|thumb|200px|right|Dame Anne Laura Dorinthea McLaren]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Beatrice_Mintz.jpg|thumb|200px|right|Beatrice Mintz]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]
[[image:Teruhiko_Wakayama.jpg|thumb|200px|right|Teruhiko Wakayama]]
[[image:Leroy_Stevens.jpg|thumb|200px|right|Leroy Stevens]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Gingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development so far a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development clink the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm.
{{Insert timeline}}
----
===Genetics===
[[image:2greenpupm.jpg|thumb|300px|right|Transgenic mouse pup]]

'''Genome'''

Sequencing of the mouse genome was completed in late 2002. Tha haploid genome is about 3 billion long (3000 Mb distributed over 20 chromosomes) and therefore equal to the size of the human genome. The current estimated gene count is 23,786 and humans are estimated to have 23,686 genes.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino.
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).
[[image:Nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome. Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.
[[image:5chris6m.jpg|thumb|300px|right|Conditional Gene Expression]]
Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function. However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

[[image:Figure3-3.jpg‎|thumb|200px|right|Examples of some commonly used mouse strains]]
[[image:Transgenicmouse.jpg|thumb|200px|right|Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition]]
Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]
[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve in mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===
[[image:NIDCR.jpg|thumb|200px|right|Members of NIDCR]]

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:

1.Supports the multiplication of the H9 cells better than the 3T3 line.

2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1/ An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155), and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on normal hematopoietic stem cells (HSCs).

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy remains uncertain until clinical trials are undertaken in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia et al. used the knockout mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knockout mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cellular differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please click [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| here] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. found that the epithelial-mesenchymal interactions in the development of the Wolffian duct and testis cord are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins, when mutated, become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin ,rather than the bacterial cell numbers, is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents, BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab, on the mice containing EGFR mutated lung tumors. It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''', which has been studied to assist in generating antibody and CD4 T helper cell responses. This process was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Haploid:''' A set of chromosomes containing only one member of each chromosome pair. The sperm and egg are haploid.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Mutation:''' is a randomly derived change to the nucleotide sequence of the genetic material of an organism.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Oncogenic:''' An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Renaturation:''' The process by which proteins or complementary strands of nucleic acids reform their native conformations.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Telocentric:''' a chromosome like a straight rod with the centromere in terminal position.

'''Transgenic:'''A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered using genetic engineering techniques.

'''Transposition:''' is a kind of mutation in which a chromosomal segment is transfered to a new position on the same or another chromosome.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Shiro, I., Meytha, M., Cristina, V., Karen, E., Walid, K., Howard, G. (2006). An immortalized drug-resistant cell line established from 12-13-day mouse embryos for the propagation of human embryonic stem cells. ''Differentiation''. Accessed from http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KJLDc4JX2vKFKSQbLw7SSJTx2pGy4dMvGQJ9zpGxDdZ5hN1YyC6H!-2135654213!181195629!8091!-1

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*Geneall. ''Dame Anne Laura Dorinthea McLaren'', retrieved September 21, 2009. http://www.geneall.net/U/per_page.php?id=557208

*Harvard University. ''Howard Green, M.D.'', retrieved September 24, 2009. http://cellbio.med.harvard.edu/faculty/green/index.html

*International Knockout Mouse Consortium. ''About the International Knockout Mouse Consortium'', retrieved September 19, 2009.

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Memorial University. ''Oration honouring Wesley Whitten'', retrieved September 11, 2009. http://www.mun.ca/marcomm/gazette/2000-2001/june14/convocation8.html

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*National Institute of Health Record. ''NIDCR Team Creates Mouse Model of Disease'', retrieved September 19, 2009. http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*University of Iowa : College of Liberal Arts and Sciences. ''Alumni Fellows'', retrieved September 26, 2009. http://images.google.com.au/imgres?imgurl=http://www.clas.uiowa.edu/_includes/images/alumni/beatrice.jpg&imgrefurl=http://www.clas.uiowa.edu/alumni/programs/fellows/2002/&usg=__ZTVwhRDWmWlpQWiTgm7QPANk0ow=&h=218&w=182&sz=10&hl=en&start=2&sig2=WxT11tEDMuSTsbeT1PzXjQ&um=1&tbnid=7WxPUu34U_wdOM:&tbnh=107&tbnw=89&prev=/images%3Fq%3Dbeatrice%2Bmintz%26hl%3Den%26sa%3DN%26um%3D1&ei=ECy2Sp_JKMiGkAX9k9XBCw

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

*Wikipedia. ''Gregor Mendel'', retrieved September 20, 2009. http://en.wikipedia.org/wiki/File:Gregor_Mendel.png

*Wikipedia. ''Rudolf Jaenisch'', retrieved September 17, 2009. http://en.wikipedia.org/wiki/File:Jaenisch_2003_by_Sam_Ogden.jpg

{{Template:Projects09}}
[[Category:Mouse]]

2009 Group Project 4

2009-10-13T10:02:07Z

Z3254857: /* References */

== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Is a small organism which can be easily maintained
*Is not expensive
----

===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:Wesley_Whitten.jpg|thumb|200px|right|Wesley K. Whitten]]
[[image:Dame_Anne_Laura_Dorinthea_McLaren.jpg|thumb|200px|right|Dame Anne Laura Dorinthea McLaren]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Beatrice_Mintz.jpg|thumb|200px|right|Beatrice Mintz]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]
[[image:Teruhiko_Wakayama.jpg|thumb|200px|right|Teruhiko Wakayama]]
[[image:Leroy_Stevens.jpg|thumb|200px|right|Leroy Stevens]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Gingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development so far a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development clink the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm.
{{Insert timeline}}
----
===Genetics===
[[image:2greenpupm.jpg|thumb|300px|right|Transgenic mouse pup]]

'''Genome'''

Sequencing of the mouse genome was completed in late 2002. Tha haploid genome is about 3 billion long (3000 Mb distributed over 20 chromosomes) and therefore equal to the size of the human genome. The current estimated gene count is 23,786 and humans are estimated to have 23,686 genes.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino.
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).
[[image:Nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome. Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.
[[image:5chris6m.jpg|thumb|300px|right|Conditional Gene Expression]]
Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function. However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

[[image:Figure3-3.jpg‎|thumb|200px|right|Examples of some commonly used mouse strains]]
[[image:Transgenicmouse.jpg|thumb|200px|right|Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition]]
Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]
[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve in mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===
[[image:NIDCR.jpg|thumb|200px|right|Members of NIDCR]]

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:

1.Supports the multiplication of the H9 cells better than the 3T3 line.

2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1/ An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155), and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on normal hematopoietic stem cells (HSCs).

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy remains uncertain until clinical trials are undertaken in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia et al. used the knockout mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knockout mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cellular differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please click [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| here] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. found that the epithelial-mesenchymal interactions in the development of the Wolffian duct and testis cord are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins, when mutated, become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin ,rather than the bacterial cell numbers, is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents, BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab, on the mice containing EGFR mutated lung tumors. It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''', which has been studied to assist in generating antibody and CD4 T helper cell responses. This process was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Haploid:''' A set of chromosomes containing only one member of each chromosome pair. The sperm and egg are haploid.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Mutation:''' is a randomly derived change to the nucleotide sequence of the genetic material of an organism.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Oncogenic:''' An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Renaturation:''' The process by which proteins or complementary strands of nucleic acids reform their native conformations.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Telocentric:''' a chromosome like a straight rod with the centromere in terminal position.

'''Transgenic:'''A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered using genetic engineering techniques.

'''Transposition:''' is a kind of mutation in which a chromosomal segment is transfered to a new position on the same or another chromosome.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Shiro, I., Meytha, M., Cristina, V., Karen, E., Walid, K., Howard, G. (2006). An immortalized drug-resistant cell line established from 12-13-day mouse embryos for the propagation of human embryonic stem cells. ''Differentiation''. Accessed from http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KJLDc4JX2vKFKSQbLw7SSJTx2pGy4dMvGQJ9zpGxDdZ5hN1YyC6H!-2135654213!181195629!8091!-1

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*Geneall. ''Dame Anne Laura Dorinthea McLaren'', retrieved September 21, 2009. http://www.geneall.net/U/per_page.php?id=557208

*Harvard University. ''Howard Green, M.D.'', retrieved September 24, 2009. http://cellbio.med.harvard.edu/faculty/green/index.html

*International Knockout Mouse Consortium. ''About the International Knockout Mouse Consortium'', retrieved September 19, 2009.

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Memorial University. ''Oration honouring Wesley Whitten'', retrieved September 11, 2009. http://www.mun.ca/marcomm/gazette/2000-2001/june14/convocation8.html

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*National Institute of Health Record. ''NIDCR Team Creates Mouse Model of Disease'', retrieved September 19, 2009. http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

*Wikipedia. ''Gregor Mendel'', retrieved September 20, 2009. http://en.wikipedia.org/wiki/File:Gregor_Mendel.png

{{Template:Projects09}}
[[Category:Mouse]]

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== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Is a small organism which can be easily maintained
*Is not expensive
----

===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:Wesley_Whitten.jpg|thumb|200px|right|Wesley K. Whitten]]
[[image:Dame_Anne_Laura_Dorinthea_McLaren.jpg|thumb|200px|right|Dame Anne Laura Dorinthea McLaren]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Beatrice_Mintz.jpg|thumb|200px|right|Beatrice Mintz]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]
[[image:Teruhiko_Wakayama.jpg|thumb|200px|right|Teruhiko Wakayama]]
[[image:Leroy_Stevens.jpg|thumb|200px|right|Leroy Stevens]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Gingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development so far a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development clink the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm.
{{Insert timeline}}
----
===Genetics===
[[image:2greenpupm.jpg|thumb|300px|right|Transgenic mouse pup]]

'''Genome'''

Sequencing of the mouse genome was completed in late 2002. Tha haploid genome is about 3 billion long (3000 Mb distributed over 20 chromosomes) and therefore equal to the size of the human genome. The current estimated gene count is 23,786 and humans are estimated to have 23,686 genes.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino.
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).
[[image:Nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome. Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.
[[image:5chris6m.jpg|thumb|300px|right|Conditional Gene Expression]]
Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function. However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

[[image:Figure3-3.jpg‎|thumb|200px|right|Examples of some commonly used mouse strains]]
[[image:Transgenicmouse.jpg|thumb|200px|right|Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition]]
Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]
[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve in mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===
[[image:NIDCR.jpg|thumb|200px|right|Members of NIDCR]]

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:

1.Supports the multiplication of the H9 cells better than the 3T3 line.

2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1/ An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155), and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on normal hematopoietic stem cells (HSCs).

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy remains uncertain until clinical trials are undertaken in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia et al. used the knockout mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knockout mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cellular differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please click [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| here] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. found that the epithelial-mesenchymal interactions in the development of the Wolffian duct and testis cord are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins, when mutated, become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin ,rather than the bacterial cell numbers, is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents, BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab, on the mice containing EGFR mutated lung tumors. It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''', which has been studied to assist in generating antibody and CD4 T helper cell responses. This process was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Haploid:''' A set of chromosomes containing only one member of each chromosome pair. The sperm and egg are haploid.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Mutation:''' is a randomly derived change to the nucleotide sequence of the genetic material of an organism.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Oncogenic:''' An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Renaturation:''' The process by which proteins or complementary strands of nucleic acids reform their native conformations.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Telocentric:''' a chromosome like a straight rod with the centromere in terminal position.

'''Transgenic:'''A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered using genetic engineering techniques.

'''Transposition:''' is a kind of mutation in which a chromosomal segment is transfered to a new position on the same or another chromosome.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Shiro, I., Meytha, M., Cristina, V., Karen, E., Walid, K., Howard, G. (2006). An immortalized drug-resistant cell line established from 12-13-day mouse embryos for the propagation of human embryonic stem cells. ''Differentiation''. Accessed from http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KJLDc4JX2vKFKSQbLw7SSJTx2pGy4dMvGQJ9zpGxDdZ5hN1YyC6H!-2135654213!181195629!8091!-1

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*International Knockout Mouse Consortium. ''About the International Knockout Mouse Consortium'', retrieved September 19, 2009.

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*National Institute of Health Record. ''NIDCR Team Creates Mouse Model of Disease'', retrieved September 19, 2009. http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

{{Template:Projects09}}
[[Category:Mouse]]

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== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Is a small organism which can be easily maintained
*Is not expensive
----

===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:Wesley_Whitten.jpg|thumb|200px|right|Wesley K. Whitten]]
[[image:Dame_Anne_Laura_Dorinthea_McLaren.jpg|thumb|200px|right|Dame Anne Laura Dorinthea McLaren]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Beatrice_Mintz.jpg|thumb|200px|right|Beatrice Mintz]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]
[[image:Teruhiko_Wakayama.jpg|thumb|200px|right|Teruhiko Wakayama]]
[[image:Leroy_Stevens.jpg|thumb|200px|right|Leroy Stevens]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Gingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development so far a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development clink the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm.
{{Insert timeline}}
----
===Genetics===
[[image:2greenpupm.jpg|thumb|300px|right|Transgenic mouse pup]]

'''Genome'''

Sequencing of the mouse genome was completed in late 2002. Tha haploid genome is about 3 billion long (3000 Mb distributed over 20 chromosomes) and therefore equal to the size of the human genome. The current estimated gene count is 23,786 and humans are estimated to have 23,686 genes.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino.
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).
[[image:Nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome. Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.
[[image:5chris6m.jpg|thumb|300px|right|Conditional Gene Expression]]
Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function. However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

[[image:Figure3-3.jpg‎|thumb|200px|right|Examples of some commonly used mouse strains]]
[[image:Transgenicmouse.jpg|thumb|200px|right|Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition]]
Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]
[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve in mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===
[[image:NIDCR.jpg|thumb|200px|right|Members of NIDCR]]

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:

1.Supports the multiplication of the H9 cells better than the 3T3 line.
2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1/ An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155), and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on normal hematopoietic stem cells (HSCs).

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy remains uncertain until clinical trials are undertaken in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia et al. used the knockout mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knockout mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cellular differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please click [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| here] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. found that the epithelial-mesenchymal interactions in the development of the Wolffian duct and testis cord are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins, when mutated, become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin ,rather than the bacterial cell numbers, is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents, BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab, on the mice containing EGFR mutated lung tumors. It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''', which has been studied to assist in generating antibody and CD4 T helper cell responses. This process was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Haploid:''' A set of chromosomes containing only one member of each chromosome pair. The sperm and egg are haploid.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Mutation:''' is a randomly derived change to the nucleotide sequence of the genetic material of an organism.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Oncogenic:''' An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Renaturation:''' The process by which proteins or complementary strands of nucleic acids reform their native conformations.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Telocentric:''' a chromosome like a straight rod with the centromere in terminal position.

'''Transgenic:'''A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered using genetic engineering techniques.

'''Transposition:''' is a kind of mutation in which a chromosomal segment is transfered to a new position on the same or another chromosome.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Shiro, I., Meytha, M., Cristina, V., Karen, E., Walid, K., Howard, G. (2006). An immortalized drug-resistant cell line established from 12-13-day mouse embryos for the propagation of human embryonic stem cells. ''Differentiation''. Accessed from http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KJLDc4JX2vKFKSQbLw7SSJTx2pGy4dMvGQJ9zpGxDdZ5hN1YyC6H!-2135654213!181195629!8091!-1

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*International Knockout Mouse Consortium. ''About the International Knockout Mouse Consortium'', retrieved September 19, 2009.

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*National Institute of Health Record. ''NIDCR Team Creates Mouse Model of Disease'', retrieved September 19, 2009. http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

{{Template:Projects09}}
[[Category:Mouse]]

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== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Is a small organism which can be easily maintained
*Is not expensive
----

===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:Wesley_Whitten.jpg|thumb|200px|right|Wesley K. Whitten]]
[[image:Dame_Anne_Laura_Dorinthea_McLaren.jpg|thumb|200px|right|Dame Anne Laura Dorinthea McLaren]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Beatrice_Mintz.jpg|thumb|200px|right|Beatrice Mintz]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]
[[image:Teruhiko_Wakayama.jpg|thumb|200px|right|Teruhiko Wakayama]]
[[image:Leroy_Stevens.jpg|thumb|200px|right|Leroy Stevens]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Gingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development so far a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development clink the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm.
{{Insert timeline}}
----
===Genetics===
[[image:2greenpupm.jpg|thumb|300px|right|Transgenic mouse pup]]

'''Genome'''

Sequencing of the mouse genome was completed in late 2002. Tha haploid genome is about 3 billion long (3000 Mb distributed over 20 chromosomes) and therefore equal to the size of the human genome. The current estimated gene count is 23,786 and humans are estimated to have 23,686 genes.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino.
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).
[[image:Nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome. Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.
[[image:5chris6m.jpg|thumb|300px|right|Conditional Gene Expression]]
Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function. However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

[[image:Figure3-3.jpg‎|thumb|200px|right|Examples of some commonly used mouse strains]]
[[image:Transgenicmouse.jpg|thumb|200px|right|Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition]]
Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]
[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve in mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===
[[image:NIDCR.jpg|thumb|200px|right|Members of NIDCR]]

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:
1.Supports the multiplication of the H9 cells better than the 3T3 line.
2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1/ An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155), and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on normal hematopoietic stem cells (HSCs).

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy remains uncertain until clinical trials are undertaken in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia et al. used the knockout mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knockout mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cellular differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please click [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| here] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. found that the epithelial-mesenchymal interactions in the development of the Wolffian duct and testis cord are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins, when mutated, become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin ,rather than the bacterial cell numbers, is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents, BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab, on the mice containing EGFR mutated lung tumors. It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''', which has been studied to assist in generating antibody and CD4 T helper cell responses. This process was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Haploid:''' A set of chromosomes containing only one member of each chromosome pair. The sperm and egg are haploid.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Mutation:''' is a randomly derived change to the nucleotide sequence of the genetic material of an organism.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Oncogenic:''' An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Renaturation:''' The process by which proteins or complementary strands of nucleic acids reform their native conformations.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Telocentric:''' a chromosome like a straight rod with the centromere in terminal position.

'''Transgenic:'''A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered using genetic engineering techniques.

'''Transposition:''' is a kind of mutation in which a chromosomal segment is transfered to a new position on the same or another chromosome.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Shiro, I., Meytha, M., Cristina, V., Karen, E., Walid, K., Howard, G. (2006). An immortalized drug-resistant cell line established from 12-13-day mouse embryos for the propagation of human embryonic stem cells. ''Differentiation''. Accessed from http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KJLDc4JX2vKFKSQbLw7SSJTx2pGy4dMvGQJ9zpGxDdZ5hN1YyC6H!-2135654213!181195629!8091!-1

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*International Knockout Mouse Consortium. ''About the International Knockout Mouse Consortium'', retrieved September 19, 2009.

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*National Institute of Health Record. ''NIDCR Team Creates Mouse Model of Disease'', retrieved September 19, 2009. http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

{{Template:Projects09}}
[[Category:Mouse]]

2009 Group Project 4

2009-10-13T09:50:19Z

Z3254857: /* Current Research */

== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Is a small organism which can be easily maintained
*Is not expensive
----

===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:Wesley_Whitten.jpg|thumb|200px|right|Wesley K. Whitten]]
[[image:Dame_Anne_Laura_Dorinthea_McLaren.jpg|thumb|200px|right|Dame Anne Laura Dorinthea McLaren]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Beatrice_Mintz.jpg|thumb|200px|right|Beatrice Mintz]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]
[[image:Teruhiko_Wakayama.jpg|thumb|200px|right|Teruhiko Wakayama]]
[[image:Leroy_Stevens.jpg|thumb|200px|right|Leroy Stevens]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Gingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development so far a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development clink the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm.
{{Insert timeline}}
----
===Genetics===
[[image:2greenpupm.jpg|thumb|300px|right|Transgenic mouse pup]]

'''Genome'''

Sequencing of the mouse genome was completed in late 2002. Tha haploid genome is about 3 billion long (3000 Mb distributed over 20 chromosomes) and therefore equal to the size of the human genome. The current estimated gene count is 23,786 and humans are estimated to have 23,686 genes.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino.
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).
[[image:Nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome. Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.
[[image:5chris6m.jpg|thumb|300px|right|Conditional Gene Expression]]
Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function. However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

[[image:Figure3-3.jpg‎|thumb|200px|right|Examples of some commonly used mouse strains]]
[[image:Transgenicmouse.jpg|thumb|200px|right|Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition]]
Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]
[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve in mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===
[[image:NIDCR.jpg|thumb|200px|right|Members of NIDCR]]

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:
1.Supports the multiplication of the H9 cells better than the 3T3 line.
2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: ''An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells''. Link to Abstract [http://www.library.unsw.edu.au/cgi-bin/Data/db.cgi?db=fulltexttest&uid=default&view_records=1&url=http://gateway.proquest.com/openurl?atitle=Harvard+University,+School+of+Medicine;+Human+embryonic+stem+cells+propagated+on+immortalized+drug-resistant+cell+line&date=2006&rft_val_fmt=ori:fmt:kev:mtx:journal&spage=236&issn=1551-529X&ctx_ver=Z39.88-2003&genre=article&res_id=xri:pqd&req_dat=xri:pqil:pq_clntid=&Address=http://gateway.proqu] or [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155), and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on normal hematopoietic stem cells (HSCs).

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy remains uncertain until clinical trials are undertaken in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia et al. used the knockout mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knockout mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cellular differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please click [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| here] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. found that the epithelial-mesenchymal interactions in the development of the Wolffian duct and testis cord are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins, when mutated, become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin ,rather than the bacterial cell numbers, is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents, BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab, on the mice containing EGFR mutated lung tumors. It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''', which has been studied to assist in generating antibody and CD4 T helper cell responses. This process was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Haploid:''' A set of chromosomes containing only one member of each chromosome pair. The sperm and egg are haploid.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Mutation:''' is a randomly derived change to the nucleotide sequence of the genetic material of an organism.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Oncogenic:''' An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Renaturation:''' The process by which proteins or complementary strands of nucleic acids reform their native conformations.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Telocentric:''' a chromosome like a straight rod with the centromere in terminal position.

'''Transgenic:'''A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered using genetic engineering techniques.

'''Transposition:''' is a kind of mutation in which a chromosomal segment is transfered to a new position on the same or another chromosome.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Shiro, I., Meytha, M., Cristina, V., Karen, E., Walid, K., Howard, G. (2006). An immortalized drug-resistant cell line established from 12-13-day mouse embryos for the propagation of human embryonic stem cells. ''Differentiation''. Accessed from http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KJLDc4JX2vKFKSQbLw7SSJTx2pGy4dMvGQJ9zpGxDdZ5hN1YyC6H!-2135654213!181195629!8091!-1

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*International Knockout Mouse Consortium. ''About the International Knockout Mouse Consortium'', retrieved September 19, 2009.

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*National Institute of Health Record. ''NIDCR Team Creates Mouse Model of Disease'', retrieved September 19, 2009. http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

{{Template:Projects09}}
[[Category:Mouse]]

2009 Group Project 4

2009-10-13T09:48:07Z

Z3254857: /* References */

== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Is a small organism which can be easily maintained
*Is not expensive
----

===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:Wesley_Whitten.jpg|thumb|200px|right|Wesley K. Whitten]]
[[image:Dame_Anne_Laura_Dorinthea_McLaren.jpg|thumb|200px|right|Dame Anne Laura Dorinthea McLaren]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Beatrice_Mintz.jpg|thumb|200px|right|Beatrice Mintz]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]
[[image:Teruhiko_Wakayama.jpg|thumb|200px|right|Teruhiko Wakayama]]
[[image:Leroy_Stevens.jpg|thumb|200px|right|Leroy Stevens]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Gingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development so far a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development clink the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm.
{{Insert timeline}}
----
===Genetics===
[[image:2greenpupm.jpg|thumb|300px|right|Transgenic mouse pup]]

'''Genome'''

Sequencing of the mouse genome was completed in late 2002. Tha haploid genome is about 3 billion long (3000 Mb distributed over 20 chromosomes) and therefore equal to the size of the human genome. The current estimated gene count is 23,786 and humans are estimated to have 23,686 genes.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino.
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).
[[image:Nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome. Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.
[[image:5chris6m.jpg|thumb|300px|right|Conditional Gene Expression]]
Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function. However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

[[image:Figure3-3.jpg‎|thumb|200px|right|Examples of some commonly used mouse strains]]
[[image:Transgenicmouse.jpg|thumb|200px|right|Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition]]
Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]
[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve in mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===
[[image:NIDCR.jpg|thumb|200px|right|Members of NIDCR]]

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:
1.Supports the multiplication of the H9 cells better than the 3T3 line.
2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: ''An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells''. Link to Abstract [http://www.library.unsw.edu.au/cgi-bin/Data/db.cgi?db=fulltexttest&uid=default&view_records=1&url=http://gateway.proquest.com/openurl?atitle=Harvard+University,+School+of+Medicine;+Human+embryonic+stem+cells+propagated+on+immortalized+drug-resistant+cell+line&date=2006&rft_val_fmt=ori:fmt:kev:mtx:journal&spage=236&issn=1551-529X&ctx_ver=Z39.88-2003&genre=article&res_id=xri:pqd&req_dat=xri:pqil:pq_clntid=&Address=http://gateway.proqu] or [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155), and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on normal hematopoietic stem cells (HSCs).

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy remains uncertain until clinical trials are undertaken in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia et al. used the knockout mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knockout mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cellular differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ here].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. found that the epithelial-mesenchymal interactions in the development of the Wolffian duct and testis cord are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins, when mutated, become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin ,rather than the bacterial cell numbers, is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents, BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab, on the mice containing EGFR mutated lung tumors. It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''', which has been studied to assist in generating antibody and CD4 T helper cell responses. This process was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Haploid:''' A set of chromosomes containing only one member of each chromosome pair. The sperm and egg are haploid.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Mutation:''' is a randomly derived change to the nucleotide sequence of the genetic material of an organism.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Oncogenic:''' An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Renaturation:''' The process by which proteins or complementary strands of nucleic acids reform their native conformations.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Telocentric:''' a chromosome like a straight rod with the centromere in terminal position.

'''Transgenic:'''A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered using genetic engineering techniques.

'''Transposition:''' is a kind of mutation in which a chromosomal segment is transfered to a new position on the same or another chromosome.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Shiro, I., Meytha, M., Cristina, V., Karen, E., Walid, K., Howard, G. (2006). An immortalized drug-resistant cell line established from 12-13-day mouse embryos for the propagation of human embryonic stem cells. ''Differentiation''. Accessed from http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KJLDc4JX2vKFKSQbLw7SSJTx2pGy4dMvGQJ9zpGxDdZ5hN1YyC6H!-2135654213!181195629!8091!-1

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*International Knockout Mouse Consortium. ''About the International Knockout Mouse Consortium'', retrieved September 19, 2009.

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*National Institute of Health Record. ''NIDCR Team Creates Mouse Model of Disease'', retrieved September 19, 2009. http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

{{Template:Projects09}}
[[Category:Mouse]]

2009 Group Project 4

2009-10-13T09:44:22Z

Z3254857: /* References */

== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Is a small organism which can be easily maintained
*Is not expensive
----

===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:Wesley_Whitten.jpg|thumb|200px|right|Wesley K. Whitten]]
[[image:Dame_Anne_Laura_Dorinthea_McLaren.jpg|thumb|200px|right|Dame Anne Laura Dorinthea McLaren]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Beatrice_Mintz.jpg|thumb|200px|right|Beatrice Mintz]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]
[[image:Teruhiko_Wakayama.jpg|thumb|200px|right|Teruhiko Wakayama]]
[[image:Leroy_Stevens.jpg|thumb|200px|right|Leroy Stevens]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Gingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development so far a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development clink the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm.
{{Insert timeline}}
----
===Genetics===
[[image:2greenpupm.jpg|thumb|300px|right|Transgenic mouse pup]]

'''Genome'''

Sequencing of the mouse genome was completed in late 2002. Tha haploid genome is about 3 billion long (3000 Mb distributed over 20 chromosomes) and therefore equal to the size of the human genome. The current estimated gene count is 23,786 and humans are estimated to have 23,686 genes.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino.
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).
[[image:Nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome. Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.
[[image:5chris6m.jpg|thumb|300px|right|Conditional Gene Expression]]
Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function. However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

[[image:Figure3-3.jpg‎|thumb|200px|right|Examples of some commonly used mouse strains]]
[[image:Transgenicmouse.jpg|thumb|200px|right|Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition]]
Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]
[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve in mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===
[[image:NIDCR.jpg|thumb|200px|right|Members of NIDCR]]

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:
1.Supports the multiplication of the H9 cells better than the 3T3 line.
2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: ''An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells''. Link to Abstract [http://www.library.unsw.edu.au/cgi-bin/Data/db.cgi?db=fulltexttest&uid=default&view_records=1&url=http://gateway.proquest.com/openurl?atitle=Harvard+University,+School+of+Medicine;+Human+embryonic+stem+cells+propagated+on+immortalized+drug-resistant+cell+line&date=2006&rft_val_fmt=ori:fmt:kev:mtx:journal&spage=236&issn=1551-529X&ctx_ver=Z39.88-2003&genre=article&res_id=xri:pqd&req_dat=xri:pqil:pq_clntid=&Address=http://gateway.proqu] or [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155), and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on normal hematopoietic stem cells (HSCs).

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy remains uncertain until clinical trials are undertaken in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia et al. used the knockout mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knockout mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cellular differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ here].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. found that the epithelial-mesenchymal interactions in the development of the Wolffian duct and testis cord are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins, when mutated, become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin ,rather than the bacterial cell numbers, is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents, BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab, on the mice containing EGFR mutated lung tumors. It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''', which has been studied to assist in generating antibody and CD4 T helper cell responses. This process was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Haploid:''' A set of chromosomes containing only one member of each chromosome pair. The sperm and egg are haploid.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Mutation:''' is a randomly derived change to the nucleotide sequence of the genetic material of an organism.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Oncogenic:''' An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Renaturation:''' The process by which proteins or complementary strands of nucleic acids reform their native conformations.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Telocentric:''' a chromosome like a straight rod with the centromere in terminal position.

'''Transgenic:'''A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered using genetic engineering techniques.

'''Transposition:''' is a kind of mutation in which a chromosomal segment is transfered to a new position on the same or another chromosome.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*International Knockout Mouse Consortium. ''About the International Knockout Mouse Consortium'', retrieved September 19, 2009.

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*National Institute of Health Record. ''NIDCR Team Creates Mouse Model of Disease'', retrieved September 19, 2009. http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

{{Template:Projects09}}
[[Category:Mouse]]

2009 Group Project 4

2009-10-13T09:42:12Z

Z3254857: /* References */

== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Is a small organism which can be easily maintained
*Is not expensive
----

===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:Wesley_Whitten.jpg|thumb|200px|right|Wesley K. Whitten]]
[[image:Dame_Anne_Laura_Dorinthea_McLaren.jpg|thumb|200px|right|Dame Anne Laura Dorinthea McLaren]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Beatrice_Mintz.jpg|thumb|200px|right|Beatrice Mintz]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]
[[image:Teruhiko_Wakayama.jpg|thumb|200px|right|Teruhiko Wakayama]]
[[image:Leroy_Stevens.jpg|thumb|200px|right|Leroy Stevens]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Gingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development so far a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development clink the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm.
{{Insert timeline}}
----
===Genetics===
[[image:2greenpupm.jpg|thumb|300px|right|Transgenic mouse pup]]

'''Genome'''

Sequencing of the mouse genome was completed in late 2002. Tha haploid genome is about 3 billion long (3000 Mb distributed over 20 chromosomes) and therefore equal to the size of the human genome. The current estimated gene count is 23,786 and humans are estimated to have 23,686 genes.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino.
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).
[[image:Nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome. Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.
[[image:5chris6m.jpg|thumb|300px|right|Conditional Gene Expression]]
Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function. However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

[[image:Figure3-3.jpg‎|thumb|200px|right|Examples of some commonly used mouse strains]]
[[image:Transgenicmouse.jpg|thumb|200px|right|Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition]]
Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]
[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve in mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===
[[image:NIDCR.jpg|thumb|200px|right|Members of NIDCR]]

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:
1.Supports the multiplication of the H9 cells better than the 3T3 line.
2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: ''An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells''. Link to Abstract [http://www.library.unsw.edu.au/cgi-bin/Data/db.cgi?db=fulltexttest&uid=default&view_records=1&url=http://gateway.proquest.com/openurl?atitle=Harvard+University,+School+of+Medicine;+Human+embryonic+stem+cells+propagated+on+immortalized+drug-resistant+cell+line&date=2006&rft_val_fmt=ori:fmt:kev:mtx:journal&spage=236&issn=1551-529X&ctx_ver=Z39.88-2003&genre=article&res_id=xri:pqd&req_dat=xri:pqil:pq_clntid=&Address=http://gateway.proqu] or [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155), and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on normal hematopoietic stem cells (HSCs).

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy remains uncertain until clinical trials are undertaken in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia et al. used the knockout mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knockout mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cellular differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ here].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. found that the epithelial-mesenchymal interactions in the development of the Wolffian duct and testis cord are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins, when mutated, become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin ,rather than the bacterial cell numbers, is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents, BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab, on the mice containing EGFR mutated lung tumors. It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''', which has been studied to assist in generating antibody and CD4 T helper cell responses. This process was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Haploid:''' A set of chromosomes containing only one member of each chromosome pair. The sperm and egg are haploid.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Mutation:''' is a randomly derived change to the nucleotide sequence of the genetic material of an organism.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Oncogenic:''' An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Renaturation:''' The process by which proteins or complementary strands of nucleic acids reform their native conformations.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Telocentric:''' a chromosome like a straight rod with the centromere in terminal position.

'''Transgenic:'''A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered using genetic engineering techniques.

'''Transposition:''' is a kind of mutation in which a chromosomal segment is transfered to a new position on the same or another chromosome.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*National Institute of Health Record. ''NIDCR Team Creates Mouse Model of Disease'', retrieved September 19, 2009. http://nihrecord.od.nih.gov/newsletters/09_16_2003/scinews.htm

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

{{Template:Projects09}}
[[Category:Mouse]]

2009 Group Project 4

2009-10-13T09:35:21Z

Z3254857: /* Current Research */

== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Is a small organism which can be easily maintained
*Is not expensive
----

===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:Wesley_Whitten.jpg|thumb|200px|right|Wesley K. Whitten]]
[[image:Dame_Anne_Laura_Dorinthea_McLaren.jpg|thumb|200px|right|Dame Anne Laura Dorinthea McLaren]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Beatrice_Mintz.jpg|thumb|200px|right|Beatrice Mintz]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]
[[image:Teruhiko_Wakayama.jpg|thumb|200px|right|Teruhiko Wakayama]]
[[image:Leroy_Stevens.jpg|thumb|200px|right|Leroy Stevens]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Gingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development so far a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development clink the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm.
{{Insert timeline}}
----
===Genetics===
[[image:2greenpupm.jpg|thumb|300px|right|Transgenic mouse pup]]

'''Genome'''

Sequencing of the mouse genome was completed in late 2002. Tha haploid genome is about 3 billion long (3000 Mb distributed over 20 chromosomes) and therefore equal to the size of the human genome. The current estimated gene count is 23,786 and humans are estimated to have 23,686 genes.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino.
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).
[[image:Nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome. Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.
[[image:5chris6m.jpg|thumb|300px|right|Conditional Gene Expression]]
Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function. However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

[[image:Figure3-3.jpg‎|thumb|200px|right|Examples of some commonly used mouse strains]]
[[image:Transgenicmouse.jpg|thumb|200px|right|Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition]]
Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]
[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve in mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===
[[image:NIDCR.jpg|thumb|200px|right|Members of NIDCR]]

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:
1.Supports the multiplication of the H9 cells better than the 3T3 line.
2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: ''An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells''. Link to Abstract [http://www.library.unsw.edu.au/cgi-bin/Data/db.cgi?db=fulltexttest&uid=default&view_records=1&url=http://gateway.proquest.com/openurl?atitle=Harvard+University,+School+of+Medicine;+Human+embryonic+stem+cells+propagated+on+immortalized+drug-resistant+cell+line&date=2006&rft_val_fmt=ori:fmt:kev:mtx:journal&spage=236&issn=1551-529X&ctx_ver=Z39.88-2003&genre=article&res_id=xri:pqd&req_dat=xri:pqil:pq_clntid=&Address=http://gateway.proqu] or [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155), and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on normal hematopoietic stem cells (HSCs).

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy remains uncertain until clinical trials are undertaken in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia et al. used the knockout mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knockout mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cellular differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ here].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. found that the epithelial-mesenchymal interactions in the development of the Wolffian duct and testis cord are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins, when mutated, become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin ,rather than the bacterial cell numbers, is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents, BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab, on the mice containing EGFR mutated lung tumors. It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''', which has been studied to assist in generating antibody and CD4 T helper cell responses. This process was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Haploid:''' A set of chromosomes containing only one member of each chromosome pair. The sperm and egg are haploid.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Mutation:''' is a randomly derived change to the nucleotide sequence of the genetic material of an organism.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Oncogenic:''' An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Renaturation:''' The process by which proteins or complementary strands of nucleic acids reform their native conformations.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Telocentric:''' a chromosome like a straight rod with the centromere in terminal position.

'''Transgenic:'''A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered using genetic engineering techniques.

'''Transposition:''' is a kind of mutation in which a chromosomal segment is transfered to a new position on the same or another chromosome.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

{{Template:Projects09}}
[[Category:Mouse]]

2009 Group Project 4

2009-10-13T09:25:01Z

Z3254857: /* Current Research */

== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Is a small organism which can be easily maintained
*Is not expensive
----

===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:Wesley_Whitten.jpg|thumb|200px|right|Wesley K. Whitten]]
[[image:Dame_Anne_Laura_Dorinthea_McLaren.jpg|thumb|200px|right|Dame Anne Laura Dorinthea McLaren]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Beatrice_Mintz.jpg|thumb|200px|right|Beatrice Mintz]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]
[[image:Teruhiko_Wakayama.jpg|thumb|200px|right|Teruhiko Wakayama]]
[[image:Leroy_Stevens.jpg|thumb|200px|right|Leroy Stevens]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Gingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development so far a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development clink the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm.
{{Insert timeline}}
----
===Genetics===
[[image:2greenpupm.jpg|thumb|300px|right|Transgenic mouse pup]]

'''Genome'''

Sequencing of the mouse genome was completed in late 2002. Tha haploid genome is about 3 billion long (3000 Mb distributed over 20 chromosomes) and therefore equal to the size of the human genome. The current estimated gene count is 23,786 and humans are estimated to have 23,686 genes.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino.
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).
[[image:Nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome. Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.
[[image:5chris6m.jpg|thumb|300px|right|Conditional Gene Expression]]
Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function. However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

[[image:Figure3-3.jpg‎|thumb|200px|right|Examples of some commonly used mouse strains]]
[[image:Transgenicmouse.jpg|thumb|200px|right|Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition]]
Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]
[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve in mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===
[[image:NIDCR.jpg|thumb|200px|right|Members of NIDCR]]

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:
1.Supports the multiplication of the H9 cells better than the 3T3 line.
2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: ''An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells''. Link to Abstract [http://www.library.unsw.edu.au/cgi-bin/Data/db.cgi?db=fulltexttest&uid=default&view_records=1&url=http://gateway.proquest.com/openurl?atitle=Harvard+University,+School+of+Medicine;+Human+embryonic+stem+cells+propagated+on+immortalized+drug-resistant+cell+line&date=2006&rft_val_fmt=ori:fmt:kev:mtx:journal&spage=236&issn=1551-529X&ctx_ver=Z39.88-2003&genre=article&res_id=xri:pqd&req_dat=xri:pqil:pq_clntid=&Address=http://gateway.proqu] or [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155), and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on normal hematopoietic stem cells (HSCs).

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy remains uncertain until clinical trials are undertaken in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia et al. used the knockout mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knockout mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cellular differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ here].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. used the mouse as a model organism to study the epithelial - mesenchymal crosstalk that occurs in Wolffian duct and testis cord development. They found that the epithelial-mesenchymal interactions in the development of these two male structures are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins when mutated become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin rather than the bacterial cell numbers is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab on the mice containing EGFR mutated lung tumors.

It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''' which has been studied to assist in generating antibody and CD4 T helper cell responses.

This process, explained above, was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Haploid:''' A set of chromosomes containing only one member of each chromosome pair. The sperm and egg are haploid.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Mutation:''' is a randomly derived change to the nucleotide sequence of the genetic material of an organism.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Oncogenic:''' An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Renaturation:''' The process by which proteins or complementary strands of nucleic acids reform their native conformations.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Telocentric:''' a chromosome like a straight rod with the centromere in terminal position.

'''Transgenic:'''A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered using genetic engineering techniques.

'''Transposition:''' is a kind of mutation in which a chromosomal segment is transfered to a new position on the same or another chromosome.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

{{Template:Projects09}}
[[Category:Mouse]]

Talk:2009 Group Project 4

2009-10-13T09:20:47Z

Z3254857: /* Changes made */

== Project Updates ==
--[[User:Z3283499|Antonio Lee]] 10:57, 2 October 2009 (EST) Hi everyone, I will be working with you during the Lab10 Tutorial and here is the news link and PDF of the manuscript for your group exercise. I encourage you to read the paper before the tutorial. Also, please indicate next to the questions below (using either your initials or student number) which one of the four questions you wish to address.
:'''Group 4 :''' [http://www.scientificamerican.com/article.cfm?id=stem-cells-from-fat-cells '''Induced Pluripotent Stem Cells Created from Fat Cells'''] in Scientific American Published online 8 September 2009 [[Media:ANAT2341_Lab10_2009_Group 4 Reading.pdf|Manuscript (PDF): Feeder-free derivation of induced pluripotent stem cells from adult human adipose stem cells]]

:Question 1. What is the background to the existing problem / disease condition?--[[User:Z3252340|Emily Wong]] 13:41, 8 October 2009 (EST)
:Question 2. What approach / method did the research team take to tackle / improve the problem? --[[User:Z3252231|Angama Yaquobi]] 19:27, 7 October 2009 (EST)(Angama Yaquobi)
:Question 3. What was the breakthrough / major advancement OR failure / drawback? and why might this be of significance?--[[User:Z3224449|Elide Newton]] 13:43, 8 October 2009 (EST)
:Question 4. What are the next steps in moving forward? What are the next or new hurdles to overcome?--[[User:Z3254857|Begum Sonmez]] 12:42, 8 October 2009 (EST)

==Constructive Criticism of Coordinator==
--[[User:S8600021|Mark Hill]] 08:07, 8 October 2009 (EST) The following comments are general in nature in no specific order, as it would be inappropriate to suggest specific changes and then assess the final project. Comments will be added during this week and you still have one week before final submission.

* The project has improved in content and layout from the original submission date.
* A general comment about images. When you click an image and it opens, the information below the image should have an explanation of what the image shows, a reference (if from a paper) and a link to the original source (if available) as well as copyright information.
* There are still issues related to page design with large white spaces visible.
* [[:File:Mice_expressing_GFP.jpg]] What is the original source of this image? Do you have permission to reuse?
* [[:File:Genetics of laboratory rodents.jpg]] What is this transgenic mouse expression pattern showing?
* The Theiler images of embryo stages are useful to have, are they really all redrawn? I will be comparing these to the original online versions and they cannot be direct copies without permission.
* [[:File:Mouse_theiler_stage8.JPG]] Reichard's menbrane?
* Glossary still incomplete.
* Reference could be tidied up.

==Constructive Criticism of Peers==

--[[User:Z3218657|Sally Clarke]] 09:59, 1 October 2009 (EST)Well Done!

I'm just jumping straight into it..

- I Think the timeline stage is fantastic - the images and information are displayed really well

- the staging information is a little cramped and thrown in together - it doesn't flow very well and the images are all over the shop

- The history section has A LOT of information an images of the scientists, what they did and how they did it - great... i know this would have taken a lot of work but its a bit long. I think maybe making it into a timeline on different pages might help this.

- The headings and sub headings are really good and informative but there is a few formatting errors which is easy to fix

- The genetics sections is really good, nice and concise yet informative

Great assignment guys!

--[[User:Z3258567|Sando Rashed]] 09:12, 1 October 2009 (EST)hey wow lots of information in this page :D, well done with the effort use all put in it looks and sounds goood, few things im not sure if it was my computer but staging of embryonic development there was just a bunch of photos and they were crammed up and overlapping each other making it very hard to read use might want to cut down on the photos in that area or scale them down to make it easier to read. you have a lot of information in your history section its good that you have what they do and their contribution to make it look a bit better you might want to split it up into a 3 way table (name/what they do/how it helped) minimise the reading as i recall dr mark saying to much reading is not something he wants he wants something more appealing to him where he can lay in bed and mark it without falling asleep so a table would be good here. other than that its a great page :D well done hope use all do well!!

--[[User:Z3223194|Bronwyn Lewis-Jones]] 08:53, 1 October 2009 (EST) Congratulations on a great assignment. There are so many good things about this page. I think the biggest (and easiest) improvement to be made is to cut down on the amount of headings for the History and Current Research. The headings used such as "What did they do?" etc are helpful in showing the reader what exactly they are to understand from what is written, however they interrupt the flow and spread out the information so that it seems rather daunting. If you can summarise each section into a few sentences then I think that will not only reduce your contents section to a more useful size but also make the page more reader friendly. If you don't like that idea you could strike a happy medium by either having you "What did they do..." to bold instead of a heading or have (in bold or italics) a very short summary sentence under the name followed by a short few sentences. This would still give the reader an impression of what do get out of each section but would increase the flow inside and between notable researchers etc. Hope you find this helpful. :)

--[[User:Z3218146|Julianna Lam]] 01:31, 1 October 2009 (EST)
- the history section is TOO long ! the structure of the history section is good, i liked the whole idea of the sub headings ie ' what did he do?' but i think you guys included way too many people in there. the layout of the history section is not very neat and very inconsistent. you provided pictures of some people but didnt provide pictures of others. there are gaps everywhere and it just looks really messy.

- the stages and timeline parts are really good. the table looks really nice. and i especially like the pictures, very well labelled.

--[[User:Z3186093|Jenny Guy]] 18:46, 30 September 2009 (EST)

Improvements:
* The history is wayyyy too long. Seriously, there are too many sub sub sub headings. Cut it down and for each scientist make it a paragraph instead of so many dot points. I almost couldnt be bothered reading them all. Definitely not a good way to represent information. Looks as though you gave up on looking for pictures of the scientists. I would too if i had that many of them. Pick the main scientists that caused a breakthrough instead of listing all 1000 of them. Also, it is inconsistent if you did decide to keep the subsubsubsub headings as 'what he did', "what he found" and "what the importance" are generally all targeting the same question.
* I think you guys are confused as your information is conflicting. Humans have 23 pairs of chromosomes. In your introduction you state they humans and mice have the same number. However in the genetics it states that mice have 20pairs. What is true?
* There are a few gaps (large random spaces) in the genetics sections. Might want to format this a little.
* For the current research see the same massive point i mentioned first....
* Your referencing in the bibliography is inconsistent. Stick with one type of system, e.g. apa OR harvard. Some of the references aren't even referenced properly. You must reference websites.
* You haven't referenced ANY of you text. How do we know you havent just cut and paste? You need to either reference within the text (e.g. Andrews, E.A. (1895) states .....) or at the end of sentences/paragraphs with (Andrews 1895) or the number used in the bibliography.

--[[User:Z3255007|Sadaf Masood]] 15:43, 30 September 2009 (EST)Hey Group 4! Congrats on your great project guys! I have listed few points that might help:

1. Very well researched History section, lots of people doin lots of work..maybe you can make it a little short as its just a little too much info on them.

2. A bit more proper formatting, lots of gaps after every picture and table, maybe you can get rid of them

3. Timeline is great, just enough info to make sense and needed.

4. 'Why use of mouse is important?' this issue is well discussed. Great work!

5. Impressive hand drawn diagrams, any chances of making them a little larger on the main page? it would look really good!

6. Glossary is also needed...will make our life easier is understanding few words.

Rest is all well guys. The current research Section is awesome, very informative and lots of details. Its a great project guys...Best of Luck!!

--[[User:Z3218792|Gabriela Pinget]] 12:59, 30 September 2009 (EST) Hello! constructive criticism as follows:

- intro is a nice ease in but needs to be edited for grammar

- wow the history section is very well researched. I like that you've included so many contributors but are you sure you need to go into so much detail? It looks a little cluttered and detracts from the overall purpose of the assignment. Think about cutting down on it a little

- I really like the ''staging of embryonic development'' section! very engaging and well formatted! well done

-I also liked the timeline of development. I like that there was not too much information at each stage, but just enough to give a clear outline. Maybe a link to find out more would be useful

- genetics section is perfect

- again, the current research section is a little too spread out. The continuous "what did they do..." works well to begin with but after a while gets to be too much

Overall, a really nice looking page

--[[User:Z3295026|Joe Nassif]] 17:59, 29 September 2009 (EST)

Awesome looking wiki page, mouse group 4 an excellent assignment.

It is a really interesting reading and viewing your wiki page the content flow really well when reviewed.

1. The assignment is impressive it outlines the point with the use of sub headings which is always useful in the project as a referencing point.

2. (What did he do?) and (What did they find?) is a great way to state the history as it allows the reader to quickly get the brief information and understand it , also the illustrations throughout the assessment was great it referred to the text really well, which supported the info impressively. The hand drawn images in the (staging) and (timeline) sections were extremely great the detail was impressive.

3. Some ways to improve the assignment:
A) There are some unnecessary data throughout the project which are not relevant for example the ‘length of mouse embryo’ , removing this sections can truncate the assignment which would enhance the structure.

B) Current research information on the background of the research finders reveal great info on the development of the model usage, the findings and the relevance to human embryology have been summarized greatly.

C) The referencing need to be fixed in proper format. Visit : www.lc.unsw.edu.au/onlib/ref_apa.html for help with APA referencing

D) a glossary is needed to help the reader understand terms.

Overall a great project. The criteria was covered really well it, stated specfic topic in regards to the mouse and it embryonic developent which group 4 has summarised really well.

--[[User:Z3295026|Joe Nassif]] 17:59, 29 September 2009 (EST)

--[[User:Z3217015|Mitchell Mathieson]] 09:39, 25 September 2009 (EST)Page looks good. I liked how there was heaps of information on the genetics and the current research (however, this was a bit too spread out maybe). There seems to be a lot of gaps in the text, so the formatting could be maybe tightened up. The references maybe should be formatted better, and there is repeated information (tables and text for stages), but I really like how clicking the image goes to another page with more information...that is cool. The drawings are cute as well. Overall very good, I think formatting was the downfall from that, but the information is top notch.

--[[User:Z3126328|Jin Lee]] 16:42, 26 September 2009 (EST) hellow group4~ very impressive assignment guys!well done! I really enjoyed reading your assignment. it was easy to read and the information was relevant. However, I found the formatting of the images and texts were too sqeezy. may be resize the images and line up with the relevant information. Also, I think the reference needs to be looked after as well. Overall, the contents of the assignment is very useful and interesting.

--[[User:Z3187802|Vishnnu Shanmugam]] 20:02, 26 September 2009 (EST)Congratulations mouse group on an excellent assignment. It is a real joy to read. One of the best features of the assignment is how it gets straight to the point with the use of sub headings “What did he do?” & “What did they find?”. Even the images used throughout the text are interesting, especially the fully labeled hand drawn images in the “staging” and “timeline” sections. Some ways to improve the assignment:

-There are some unnecessary graphs in the assignment such as “the average length of mouse embryo”, “number of cells” and “number of somites”. These could perhaps be combined into a single graph. It will also reduce the congested appearance of the assignment as it seems too densely packed with no particular focus.

- In current research section, it is advisable to reduce the number of research and focus on just a few but provide more comprehensive information on the background of the research, the findings and the relevance to human embryology. It currently contains too many different types of research that have described very briefly.

- Edit the "content" section at the top of the page as it's length seems to be getting out of control. It is perhaps better to exclude the sub headings “What did he do?” & “What did they find?” in the contents.

- The referencing in the text need to be completed as there are some sections well referenced and others with no referencing. see www.lc.unsw.edu.au/onlib/ref_apa.html for help with APA referencing

- A Glossary would also complement the text.

Overall a classy project, only some changes necessary

--[[User:Z3126345|Gang Liu]] 16:49, 27 September 2009 (EST)This is one of the better wikipage i have seen so far. It demonstrates not only extended literature research skill, but also an in-depth understanding of the topic. The content of this page has been consistent throughout. In addition, paragraphs are straigtforward and concise, and make the point. Detailed texts with accessory graphics are appropriate in here. In paticular, history section. It describes the model use in terms of details of experiment, and results of experiment. Stages and timeline are very self-explanatory and visually enhanced.

This project can be improved by considering the following points.

*Lack of glossary list. Need to provide meaning of words such as "polyestrous", "oocyte", "Ectoderm", "endoderm", etc;

*Reformat stages section. I found this section a bit "busy". Might considering resize the pictures.

Last few words. I have learnt from this page that mouse has the same size genome as the human genome; Mouse genes can be easily manipulated and studied; Mouse a high degree of homogeny with humans. Well done!

--[[User:Z3217686|Thomas Dangerfield]] 14:12, 28 September 2009 (EST)Hey guys! Wow so much info first off! Not entirely sure we need to know about everyone involved in the history, maybe could have collaborated and joined people together or possibly even left certain people out. To me, the whole page is like how mark described, with everything all one great smudge of info with no real formatting or sequence or continuation. It was just kind of like an overload and reading it was a little difficult at some stages. Also corresponding the images in the timeline could have been included in the text.

Also I think your numbering of figures is a little off in the timeline section, with figures 1-4 on the right and then you have figures 4-7 describing stages 12-14. Just seems that there is two figure 4's for two different images.

Love the large amount of research and information, but could just work on your presentation and you'll do fine! Great work guys!

--[[User:Z3185685|Sumaiya Rahman]] 16:56, 28 September 2009 (EST) Hey guys! Overall a very nice assignment with a great deal of information! You can tell you guys did a lot of research. The contents are massive! Maybe you could cut this down and not use so many subheadings such as “what did they do?”, “what did they find?” and only have a subheading for each researcher. The introduction is well written. The history of model use has some really good information. My only criticism in this section is that there are a lot of gaps and blank spaces. You just need to delete all the spaces. The staging section showed a lot of research and effort. Well done!! The only thing is, is it a bit too much? There are a lot of tables and images that it was hard to keep track. Maybe this could be set out differently and made to look less busy. The timeline of development is fantastic and set out really well. It is very easy to understand and the drawings are great! Once again the current research is very spread out with lots of spaces. Also adding a glossary may help the readers in understanding the text. GREAT JOB!

--[[User:Z3215682|Carly Mooney]] 11:49, 29 September 2009 (EST)
I think all your material is there but the page layout needs work. Especially the history of the models use.
*The spacing and images are inconsistent. I liked the history of timeline section information and how it was presented, just the spacing of it all needs to be even.
*The stages of embryonic development was a little all over the place, and very daunting to look at.
*A glossary would help.
I think you guys did a really good job and just have to work on presentation.

--[[User:Z3220040|Joanne Raffel]] 16:14, 29 September 2009 (EST) Very impressive page, however it was very long!!! The introduction was very clear and concise. The history section was extremely long and poorly formatted, there were too many pictures with too little information, I would recommend cutting some of the images and just keeping the pictures of those who made a significant impact upon the mouse embryo, I also thought it was unneccessary to write after each subheading, what did he do and their result, I would prefer if it was just one paragraph. Your main heading were overshadowed by the subheadings and the rest of the text. There is a lot of information for the staging section, which is good however it can made it difficult to read, I would recommend having some of the information linked onto a separate page. The picture and format for the timeline section was exceptional however it lacked information, I also thought that it was irrelevent rewriting the timeline after the pictures, I would recommend including it with the picture rather than after it and the graph size made it seem insignificant. The genetics section was very extensive and I thought some of the information was better included with the current research. Similar to the history section, I thought the formatting of the current research section was very unorganised and too spaced out. Overall a very nice page.

----

--[[User:S8600021|Mark Hill]] 01:46, 8 September 2009 (EST) Well the content is there now, but what a mess, and I am not just talking about the formatting problem which can be easily fixed, you have no structure to your project, its not a matter of throwing everything at a wall and seeing what sticks. Work together for an integrated coverage. Timeline of development, is not the way to start your page with a huge table of data.

--[[User:S8600021|Mark Hill]] 08:43, 21 August 2009 (EST) OK guys, time to see some actual content uploaded on both your discussion and project pages.

* Timeline of Development - how long (Emily)
* Staging - are there species specific staging, what occurs when (Elide)
* History of Model Use - when was it first used, what embryology research (Begum)
* Genetics - chromosome number, sequencing (Angama)
* Current Embryology Research - research papers and findings (All)

Here is a link for timeline
[http://books.google.com.au/books?id=XLIarRWHikAC&pg=PT199&lpg=PT199&dq=mouse+embryo+development+timeline&source=bl&ots=fobLBRiacx&sig=cK4cuZah6Ksczs3o8v4NXQqoAyk&hl=en&ei=rGB6SvTHMMmIkAXB_piAAw&sa=X&oi=book_result&ct=result&resnum=3#v=onepage&q=&f=false
]

link for the mouse brain development timeline http://en.wikipedia.org/wiki/Mouse_brain_development_timeline

hey guys there is another interesting link about mouse development http://mouseatlas.caltech.edu/index_content.html

Hey Emily. The link below has a timeline that you can check out in your spare time. Begum.
[http://books.google.com.au/books?id=4juoa5xMs8oC&pg=PA31&lpg=PA31&dq=mouse+embryology&source=bl&ots=9tJAfRG4R6&sig=hjR5Zs-sL1sCW5FY8FnR5TMaUk0&hl=en&ei=LuuMSr_aCNjakAX714icDA&sa=X&oi=book_result&ct=result&resnum=9#v=onepage&q=mouse%20embryology&f=false]

Hi girls,
here is a link to a text book about mouse embryology it looks pretty good. hope it can help
[http://books.google.com.au/books?id=4juoa5xMs8oC&printsec=frontcover&dq=mouse+development&source=gbs_similarbooks_r&cad=2#v=onepage&q=mouse%20development&f=false]
let me know if the link doesnt work. Ive been working on the main page, so have a look and tell me what you think, Also what are we doing about references? If we have used information but put it in our own words do we need to put in text citations,or do we just reference the journal at the end? I just want to be very careful. Thanks!

Hey Elide, i think your work is looking really good. its very easy to read and understand. keep going!!!! emily

hey everyone,
I have uploaded some of my timeline work. I'm not sure if I've gone into to much detail or not and also on how is best to present the timeline. It is fairly basic and definately needs some work - especially on presentation, grammar, etc. let me know what you think.
Emily

good site for stages or timeline- atlas of pictures of stages- The Edinburgh Mouse Atlas Project [http://genex.hgu.mrc.ac.uk/]

Hello girls, it's Begum. I put some info under the history section. Wanted to let you all know that I've got a fair bit of info, and I will do my part as best as I can. Btw Emily, I think maybe dot from would be best for you, but if you can use those lines that I was talking to you about on Wednesday, that would be great...I know it's hard.

hey everyone, i have put some info under the genetics heading and some under research. I am still struggling to find the appropriate info related to the topic of genetics because there is alot of info abt the different types of stains used in labarotories but not the genetics. I emailed Dr.Hill and have asked him what to include in my section specifically,hopefully he will help. So far i have just started it needs alot of more work to be done,girls just read thru my section n leme know wt u think of it. have a nice weekend everyone. Angama.

Hi girls!
Begum, you history info is really good. If very interesting! I really like how you are doing it in order of dates of discovery and what they did, what they found etc! Cant wait to know more.
Angama, your doing well! it sounds like your finding the info hard to get. I'll keep an eye out for you! If your stuck on what you sound be doing then i might have a few ideas. I remember Mark Hill saying that you should compare the genome to the humans genome. so maybe if the genome is the same size as the humans, could you descibe similarities or differences? I know that there is a link to the mouse genome on the mouse web page he gave us ( next to the discussion link). Are you just ment to list the mouse genome sequence? could you go into what genes code what, eg which one codes for the sex linked gene, is it the X and Y gene etc? hopefully Mark gives you some ideas.
well as you might have noticed i've been adding to my stages. the only thing is im worried about there being too much info up there. basically ive tried to get all the info available included in my stages to make sure i cover everything, and then later i'll go over it all and edit and polish it up a bit. Ive done some drawings to the best of my ability, but i can scrap them if you all think they arnt professional enough. just thought i'd try to present the information differently. let me know if you think i'm including too much information. i think i'm having the same problem as you begum, there is lots of info! Elide

Thanks Elide. I'm trying. (Again, loved the artwork!)Btw, Emily, I had a think about your section and I think it might be too much 'clicking' back-and-forth if we link the displayed pic to the 'info' page. Don't stress, you've got the info (heaps which is excellent) but make sure you get some pictures soon so we can start drawing (I'm helping with the drawings as well ok). Mark said 'Nature' and 'Science' have useable images so lets make that our start.
BTW, I will be using the question mark symbol(???) so I don't forget to reference. Begum

Hey everyone, I have found an online text book. it has a chapter on genetics and history and a lot of other stuff. [http://books.google.com.au/books?id=Vt6nUmz1yEQC&pg=RA1-PA207&dq=mouse+development+anatomy&client=firefox-a#v=onepage&q=mouse%20development%20anatomy&f=false] Emily

Hey girls. If you've seen my section, the info is not on the main page, but linked to another page. I thought that it might make everything look more neat. I thought we could all do it like that. It's just an idea. Something different. Maybe we could have something on the main page (picture of a mouse). Your thoughts everybody? Begum

hey begum, ur work looks really good. i like the idea of linking the work to another page. - we don't have to worry about to much info being on the front page and it gives people to option of viewing the work if they want to. ive been working on drawings, i'll show them to you next week but am not sure how to upload them at the moment. Emily

Thanks! That sounds great that you like the idea. About the photos that you are drawing, if there by hand, you can scan them somehow. But overall,
1. click 'Upload File' on the left hand side of this page
2. New page comes up: click 'Browse' and choose your file that you want to upload.
3. Name it (under the Browse button)
NOTE: write down what you named the file as because like Elide says "...it's going to be lost in space!..."
4. Write down info/comments (like who is the author (YOU), and if the drawing is based on a picture)
5. UPLOAD!
6. Go to your section and just normally type this down to the area you want the picture to be seen:
[[image:THE NAME THAT YOU SAVED THE FILE UNDER.jpg|thumb|200px|right|WHAT YOU WANT THE FILE NAME TO VISUALLY COME UP AS]]

Your thoughts Angama and Elide? (about the linking of our sections to separate pages?) Begum.

Oh and another thing:
What do you girls think about my page, I've got a heading for each DATE and underneath each there are further subheadings (e.g. 'What did he do?'. Should I change them to just text, I mean, does it look messy with sub-sub-headings? Begum.

wow girls! great work.. okay so i asked mark about a new page and he said to avoid it because our info is meant to be on our one page. he said if there is extra information on what we wanted to say but is too much for the main page then have a link to our discussion page. (which is what im going to do) Begum your new page is fantastic!! you have done lots of work! but why dont you just put it on our main page? also girls i think we are getting too carried away with info. just keep it simple! i'm sorry i havent been around this week to work on it but i plan to get going asap. just fixing up some things, summarising, writing introductions etc.
did you all read his note about slabbing info onto our page?? how about some introductions, and sentences to ease ourselves into the content. planning on trying to work on that now anyway..

also lets get the information flowing. why dont we go intro, history of model use, stages, timeline, genetics, then current use.. what do you all think?

hey, i thing that that sounds like a good, logical way to do the page. i've finished the drawings, just need to upload them. About the timeline information, is there anything specific that i should include. the stuff that is on the page is a little vague and so i need some advice as to what are key points that i should include. i know that the drawing are very simplistic, let me know wjat you think about them. ive put one up below. i just need a way to link it to text. emily

Thanks Elide. You know, I think that's a great idea. Have it all on one page, seems less 'diverging...', seems more COMPLETE. I love the ORDER as well. I'll fix all that up!

Hey girls, please have a look at what i've done on the timeline. the images are all hand drawn based upon the text: 'the house mouse'. if anyone could give me any ideas on how best to present the pictures - which would be better - next to or below the text? keep in mind that it is incomplete and there is an illustration for each day of development (i.e. 19 in total). if you think that is too many let me know, some may be similar to Elide's ones. Also, do you think i should put some colour into the drawings? Emily

I love your work Emily. All you need to do is put the info on the growth of the mouse that is on the main page, onto the page with the graph of the growth of the mouse embryo...we talked about that before any way-AND I think your parts finished! Begum.
Angama, I added something to the end of your section that I thought was interesting. Have a look. And are you mentioning manipulation and 'shut-down' of the genes in your section?? Begum.
To everyone, apparently ''Mus Musculus'' is the scientific name of the common house mouse, not the mouse. I was thinking of editing that.

HEY EVERYONE! well i've added in some pictures just to make it look more visual, change them if you have better ones.. and i'm going to be working on the current research section tommorow. oh i also added some graphs like we thought of for emilys section.. so i think my section is finished finally! what do you think? can i just say, I think the whole thing looks great! you girls have been a pleasure to work with! :) Thanks so much!!

hi girls, i am sorry..i have been very busy during the mid-sem break and i know we all had our exams and assignments due. but i was having some issues in my family and also the exams and assignments so didnt really had the chance to read wat u girls have got on the main page. i just finished reading thru it and it looks amazing..WELL DONE GIRLS!! you all have done a marvellous job...Eldie and Begum thanks for suggesting some main points to add for the genetics.i am currently working on it.. hopefully tonight i will have all the information on the page..Begum i love how you have presented alot of info into a very easy and understandable way..it makes so much sense..n it looks very nice with the pictures. Eldie and Emily great amount of work and the pictures and the graphs are superb. i just had a look to other groups pages. n i think so far our page looks very interesting with concise info n amazing pictures. n Begum yes i read what you have added thanks for tht..i will cu girls around..gudluck everyone. cheers. Angama.

Girls can you please help me out.. i am so annoyed..
like rite now i was typing some info and when i clicked to save.
it says "conflict" so i think some one else is also editing
the page at the same time that i am. and i lost all my work..arghh..
so which means i have to type it all again.
is there any other way that it tells me that someone else
is also using it so i dont click on save or even preview
because when i do tht i lost all the work tht i had.
If anyone knows please let me know. thanks. Angama.

Current research : I have put some information in the current research part. not sure where they should be put. Begum, as discussed you can edit it or place it in its appropriate place.

Don't stress Angama at all, now you know, it will be over soon. Uploading it easy:

1. click 'Upload File' on the left hand side of this page

2. New page comes up: click 'Browse' and choose your file that you want to upload.

3. Name it (under the Browse button) NOTE: write down what you named the file as because like Elide says "...it's going to be lost in space!..."

4. Write down info/comments (like who is the author (YOU), and if the drawing is based on a picture)

5. UPLOAD! 6. Go to your section and just normally type this down to the area you want the picture to be seen:

It's easier than it is typed! Of you still have problems I will be at the embryo lab, of there is exams there the ANAT LAB opposite to it, if not Level 3 library computers.

[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19538749| maternal diabetes alters transcriptional programs in the developing embryo], [http://www.ncbi.nlm.nih.gov/pubmed/19414407?ordinalpos=35&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum|Abnormal mammary gland development in MMTV-CBLC transgenic mouse], [http://www.ncbi.nlm.nih.gov/pubmed/19394325?ordinalpos=40&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum|Sonic hedgehog signalling inhibits palatogenesis and arrests tooth development in a mouse model of the nevoid basal cell carcinoma syndrome.], [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=55&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum| Fibroblast growth factor 18 gives growth and directional cues to airway cartilage.]

Hi girls, i think i have completed my section. could you all please just read thru it and leme know wat you think of it. i did it to the best of my ability. Hopefully you will all like it if you girls think therez anything more to add or to delete leme know..thanks. gudluck girls. Angama.

Angama your work is fantastic! Thanks so much! im sorry i wasnt around to help you with the problems. hope it went okay. your info is perfect! im very happy with our page! lets hope everyone else is :)

I love it Angama, good work! And the pictures you uploaded are very interesting. Cool. Awesome. Your done!! Begum.

Thanks Begum :) Girls gudluck and cu all tomorrow. Angama.

== Discussion after peer assessment and constructive criticism ==

Hi girls,
Ive started making some changes to the page based on the comments recieved.
Note i've also started a glossary of terms. Also many of our comments regarded our references,so It would be great if we could all reference the same, lets say APA because this is the most common way for referencing. I have gone through our references and tried to format them in APA. many are incomplete references so i have bolded the references that are missing detail. please if you all could complete your references that you added to the list. Also shall we number the references so we can include the numbers in the text as in text references? like foot note? what do you all think... there have been many comments on our current research page.. so how would you all like to fix it? I personally think its way too much. It seems to have accumulated heaps of info from when I last saw it. Is there anyway of summarising the current research info to focus more on how they are used rather than the institute and scientists involved. I think the most important info in this section is what mice are being used to discover currently and proof of the year of study. Cant wait to hear what you all think! Elide

one more thing.. ive tried to edit the contents, as one of our peers suggested, however i cant seem to edit it. do any of you know how to do this?
Elide

hey emily, i see you have reduced the heading in the contents!! thats great! i was just thinking that maybe we dont need so many headings in those 2 sections at all. what do you think about just making all the scientists and the names of people/ labs just in bold.?

Hi girls, have a look at the changes i have made to my section. let me know what you think. Emily

looks good!!
also girls could you please add words from your sections to the glossary, as that whole list is only from the staging section. thanks. elide

Hello girls. I will be re-formatting the history section in order to get rid of the 'gaps' that my peers have mentioned. Also, Elide mentioned yesterday that placing all the 'History' pictures towards the right-side of the page would look more neat, as well as add to the flow of the page. I think this is a great idea. Begum. Oh, and '''what do you guys think about taking out some information (findings)?''' Some students have mentioned that there is too much information/researchers.
And Elide, I'm might change the names of the researchers. like you said before, to bolded text. It would look much more neat. I might, also, '''apply this to the Genetics section. What do you all think?'''

'''Begum's Problem'''
Hey. I placed all pictures to the right-hand side (history section), but the pictures don't correspond well with the text. Any suggestions?? Should I than put the towards the left? Love the change to the timeline section Emily.

HEY BEGUM!!
so your problem.. I dont think the pictures need to match up because if they have a title of the person then the reader can find their picture. plus the comments are on the spaces and gaps between text, not the pictures.. so maybe just put them all underneath each other and even if they dont match up then at least the writing looks more organised. try making the images 200px and not so large and it could work better?. also the bit about taking out the headings in the genetics would be great!! bold would still look fine! goodluck! xox

--[[User:Z3254857|Begum Sonmez]] 14:54, 10 October 2009 (EST) '''TO ELIDE''': I was going to change the headings 'Reproduction' and 'Theiler Stages' under STAGES to bolded text. What do you think? Plus, like you said before, I'm on that ref. list, I will summarise the current research, and change those headings. If the HISTORY pictures match up to the the text, it would be more convenient for the viewer, don't you all think so??? However, the text would appear better the other way with the images al together on the right. Yes, I'll do that.

Hey '''Begum'''!
yes what a great idea about changing the headings in the staging section! the whole page needs to have the same structure throughout! I shall change them right now! :) i'm a little confused about the bit you said about what you said about the ref list. do you mean that you will fix yours? ive been through some of them and looked up the missing details. some are lacking their full reference though. but that would be so great if you could fix up your references. i think the ones in bold are the ones still needing work, but correct the others if you think they arent finished.
well i think the history section looks great! even though the pictures dont match up, they are still there and they look neat and have the same format as the rest of the page. and even better there are no spaces! so it looks great!! i wouldnt worry too much, you've done a such great job providing detail, the pictures are just a bonus!
the reference list looks great! thanks for your help! xox Elide

--[[User:Z3254857|Begum Sonmez]] 20:55, 11 October 2009 (EST)Hello girls! One more thing left: Current Research section. One student said to reduce the number of 'research', but include more information on each. I don't think adding more info under the research is necessary. But '''just keeping the 'breakthroughs'''' would be good, the more important ones. What do you all think? Also, '''what should the headings be''', any suggestion? Should I keep the Organisations as the headings, or the names of the researchers involoved, and/or the dates?

--[[User:Z3224449|Elide Newton]] 11:41, 12 October 2009 (EST) hey. about the current research section. well now that it doesnt have as many spaces and gaps it doesnt look as long, so maybe thats why the student saids to reduce the number of examples. so i'm with you begum, keep the important ones. for example if there are 2 examples of its use in cancer then have only one cancer example. yes headings . i think maybe keep the organisation and date. see what the other girls think.. i'll have a think about it too, and see what we can improve on that section.. overall are we all happy with how its looking? i think its looking great! even the reference list doesnt look messy! :)

--[[User:Z3224449|Elide Newton]] 14:48, 13 October 2009 (EST) Begum! your work is amazing! the current research section looks so much better! I think the page is starting to come together now! what i plan on doing is giving the whole thing a good proof read to make sure the flow, format, text, and info is consistent throughout. what else should we do with it. is everyone liking the improvments so far? dont forget we only have tomorrow to work on it!

--[[User:Z3254857|Begum Sonmez]] 19:43, 13 October 2009 (EST)
Thanks Elide!! I have and will continue proof reading the history and current research section (for any mistakes and grammar issues), so you don't need to proof read those sections in-depth (save you time). Just to let you all know, I may or may not get rid of some current research findings. I think we all did a great job, and our page looks very organised and professional. Well done to all of us.

== List of things still to do ==
* proof read the whole thing
* check if your images have info underneath, reference and copyright liscence (Angama you might need to check your genetics pictures.) If your busy I can do them for you but i need to know the reference and copyright permission. Elide

== Changes made ==
--[[User:Z3224449|Elide Newton]] 12:17, 2 October 2009 (EST)
*Removed table of stages from discussion page
*Corrected introduction " the mouse has a similar genome to the human"
*In stages section changed size of images to 200px and moved to the right
*Removed spaces and gaps from stages
*Formated stages section to look neater
*Deleted the links to tables on discussion page
*Added in table of theiler stages 12-14 which was on the discussion page
*Started a glossary of terms
--[[User:Z3224449|Elide Newton]] 16:17, 5 October 2009 (EST)
*Added in text citations to the staging section
*Added in more definitions for glossary of terms and referenced glossary
*Went through each reference of reference list and changed the format it into APA, bold for incomplete references.. to note that it needs to be fixed.

--[[User:Z3252340|Emily Wong]] 11:28, 6 October 2009 (EST)
* Edited the contents so that it wasn't as long i.e. took out all the repeated "what did he do?" etcs.
* Edited current research so that contents are not as long. Again taking out the "what did the do" etcs.
--[[User:Z3252340|Emily Wong]] 15:38, 8 October 2009 (EST)
* Edited the timeline of development section by:
** Taking out the written text and incorporated it into the captions below each drawing.
** Rearranging the work so that it was in a better position
** Linked the graph 'Average length of the mouse embryo' into the section by writing a small blurb on it.

--[[User:Z3224449|Elide Newton]] 10:44, 9 October 2009 (EST)
* Removed spaces in sections current research and genetics
* Moved images to the right and changed size to 200px in current research section
* re-uploaded theiler stage 8 image with typo fixed ( reichards to Reicherts)
* added information below images in the staging section.
* added links to source below images in staging section
* deleted 'Photo of mouse vascular development at Theiler stage 20' because I am unable to find copyright liscence
* went through each ref and chagned to APA, had to look up dates and authors for incomplete references added by other students. still some are not complete (in bold) so if you added these references could you please fix.

--[[User:Z3254857|Begum Sonmez]] 12:28, 9 October 2009 (EST)
*Changed the heading 'Chromosome number and banding patterns' under Genetics, from being a main heading to a sub-heading. This was a small mistake that had to be fixed.
*Changed the sub-headings of the history section, that list the years, to bolded text. The reason for this change is that it condensed the amount of headings in the 'Contents', allowing the viewer to have an outline of the page instead of a massive list of each heading. As a result, the page looks more neat, and each section is consistent with eachother.
*Placed all pictures in the History section to the right-side of the page. This is more consistent with the rest of the page, and adds to the flow of the page.
*Placed 2 spaces between each finding, and 1 space between each part of the finding (For example, 'What did they find', 'The Importance'). Again, this is another feature which adds to the consistancy of the page. Many of our peers pointed out that our page was messy. This change helps to solve the problem.

--[[User:Z3224449|Elide Newton]] 20:38, 9 October 2009 (EST)
*Removed headings from current research section and made them bold.
*Finished the glossary of terms from the staging section
*worked on current research. (removed spaces, formated, removed lists of names and added 'et al')

--[[User:Z3254857|Begum Sonmez]] 14:45, 10 October 2009 (EST)
*Changed the sub-headings under the Genetics section to bolded text. There were no complaints about this from our peers. However, since this was applied to the History section, applying it to the Genetics section would be consistent and more neat.
*Placed all HISTORY pictures beneath one another in order to be consistent with the arrangement of other pictures throughout the page.
*Deleted some of the headings (what did they, how did they...) under the history section, as the contents of some of the headings were related. One student mentioned this. As a result, there is less headings, and a greater degree of clarity.
*Edited the Reference list by dividing it into 2 headings ('Books and Articles' and 'Webpage'), and converted some more references into APA style. Just one more conversion left.
*Added the definitions of 'Allophenic', 'Chimera', 'Corpus luteum', 'Somatic tissue' and 'Stem Cell' to the Glossary List.

--[[User:Z3224449|Elide Newton]] 19:44, 10 October 2009 (EST)
*Removed headings from staging section and made bold instead to be the same as the whole page
*Removed two gaps from the genetics section

--[[User:Z3254857|Begum Sonmez]] 14:24, 12 October 2009 (EST)
*Changed some of the Sub-headings under the Current Research section to make it more consistent throughout this section.
*Converted the information under each finding under the Current Research section into numerous small paragraphs because one student outlined that the use of the sub-sub-headings were good at first, but it than became overwhelming. This change enhanced the layout without using the sub-sub-headings and without ending up with a slab of text.

--[[User:Z3254857|Begum Sonmez]] 11:18, 13 October 2009 (EST)
*Changes the heading 'THE MOUSE' from all upper-case to lower-case. This is consistent with the other main headings.

--[[User:Z3252231|Angama Yaquobi]] 19:35, 13 October 2009 (EST)
*Removed some of the images in the genetics section because there was not much information about the image.
*Replaced those images with new images containing information about the image.
*Added the definition of 'Haploid', 'Mutation', 'Oncogenic', 'Renaturation', 'Telocentric', 'Transgenic', and 'Transposition'.

--[[User:Z3254857|Begum Sonmez]] 20:20, 13 October 2009 (EST)
*Changed the word 'Are' to 'Is' under the introduction. Just a slight grammatical mistake.
*Added to the comment under the Gregor Mendel picture under the history section, the words 'Copyright has expired'. This informs the reader/viewer about the copyright information.
Proof read the Current Research section. Changed a few grammatical mistakes, and deleted unnecessary sentences. This shortened the content of each finding, providing a summary of the key points for the audience.

2009 Group Project 4

2009-10-13T09:14:40Z

Z3254857: /* Current Research */

== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Is a small organism which can be easily maintained
*Is not expensive
----

===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:Wesley_Whitten.jpg|thumb|200px|right|Wesley K. Whitten]]
[[image:Dame_Anne_Laura_Dorinthea_McLaren.jpg|thumb|200px|right|Dame Anne Laura Dorinthea McLaren]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Beatrice_Mintz.jpg|thumb|200px|right|Beatrice Mintz]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]
[[image:Teruhiko_Wakayama.jpg|thumb|200px|right|Teruhiko Wakayama]]
[[image:Leroy_Stevens.jpg|thumb|200px|right|Leroy Stevens]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Gingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development so far a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development clink the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm.
{{Insert timeline}}
----
===Genetics===
[[image:2greenpupm.jpg|thumb|300px|right|Transgenic mouse pup]]

'''Genome'''

Sequencing of the mouse genome was completed in late 2002. Tha haploid genome is about 3 billion long (3000 Mb distributed over 20 chromosomes) and therefore equal to the size of the human genome. The current estimated gene count is 23,786 and humans are estimated to have 23,686 genes.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino.
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).
[[image:Nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome. Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.
[[image:5chris6m.jpg|thumb|300px|right|Conditional Gene Expression]]
Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function. However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

[[image:Figure3-3.jpg‎|thumb|200px|right|Examples of some commonly used mouse strains]]
[[image:Transgenicmouse.jpg|thumb|200px|right|Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition]]
Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]
[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve in mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===
[[image:NIDCR.jpg|thumb|200px|right|Members of NIDCR]]

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:
1.Supports the multiplication of the H9 cells better than the 3T3 line.
2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: ''An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells''. Link to Abstract [http://www.library.unsw.edu.au/cgi-bin/Data/db.cgi?db=fulltexttest&uid=default&view_records=1&url=http://gateway.proquest.com/openurl?atitle=Harvard+University,+School+of+Medicine;+Human+embryonic+stem+cells+propagated+on+immortalized+drug-resistant+cell+line&date=2006&rft_val_fmt=ori:fmt:kev:mtx:journal&spage=236&issn=1551-529X&ctx_ver=Z39.88-2003&genre=article&res_id=xri:pqd&req_dat=xri:pqil:pq_clntid=&Address=http://gateway.proqu] or [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155), and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on normal hematopoietic stem cells (HSCs).

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy remains uncertain until clinical trials are undertaken in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia, et al. used the knock out mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knouck out mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cell differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ here].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in critical developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. used the mouse as a model organism to study the epithelial - mesenchymal crosstalk that occurs in Wolffian duct and testis cord development. They found that the epithelial-mesenchymal interactions in the development of these two male structures are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins when mutated become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin rather than the bacterial cell numbers is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab on the mice containing EGFR mutated lung tumors.

It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''' which has been studied to assist in generating antibody and CD4 T helper cell responses.

This process, explained above, was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Haploid:''' A set of chromosomes containing only one member of each chromosome pair. The sperm and egg are haploid.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Mutation:''' is a randomly derived change to the nucleotide sequence of the genetic material of an organism.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Oncogenic:''' An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Renaturation:''' The process by which proteins or complementary strands of nucleic acids reform their native conformations.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Telocentric:''' a chromosome like a straight rod with the centromere in terminal position.

'''Transgenic:'''A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered using genetic engineering techniques.

'''Transposition:''' is a kind of mutation in which a chromosomal segment is transfered to a new position on the same or another chromosome.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

{{Template:Projects09}}
[[Category:Mouse]]

File:Gregor Mendel.png

2009-10-13T08:50:23Z

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Image of Gregor Johann Mendel. Internet Link: [http://en.wikipedia.org/wiki/File:Gregor_Mendel.png]
Copyright has expired.

File:Gregor Mendel.png

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Image of Gregor Johann Mendel. Internet Link: [http://en.wikipedia.org/wiki/File:Gregor_Mendel.png
Copyright has expired.

Talk:2009 Group Project 4

2009-10-13T08:43:58Z

Z3254857: /* Discussion after peer assessment and constructive criticism */

== Project Updates ==
--[[User:Z3283499|Antonio Lee]] 10:57, 2 October 2009 (EST) Hi everyone, I will be working with you during the Lab10 Tutorial and here is the news link and PDF of the manuscript for your group exercise. I encourage you to read the paper before the tutorial. Also, please indicate next to the questions below (using either your initials or student number) which one of the four questions you wish to address.
:'''Group 4 :''' [http://www.scientificamerican.com/article.cfm?id=stem-cells-from-fat-cells '''Induced Pluripotent Stem Cells Created from Fat Cells'''] in Scientific American Published online 8 September 2009 [[Media:ANAT2341_Lab10_2009_Group 4 Reading.pdf|Manuscript (PDF): Feeder-free derivation of induced pluripotent stem cells from adult human adipose stem cells]]

:Question 1. What is the background to the existing problem / disease condition?--[[User:Z3252340|Emily Wong]] 13:41, 8 October 2009 (EST)
:Question 2. What approach / method did the research team take to tackle / improve the problem? --[[User:Z3252231|Angama Yaquobi]] 19:27, 7 October 2009 (EST)(Angama Yaquobi)
:Question 3. What was the breakthrough / major advancement OR failure / drawback? and why might this be of significance?--[[User:Z3224449|Elide Newton]] 13:43, 8 October 2009 (EST)
:Question 4. What are the next steps in moving forward? What are the next or new hurdles to overcome?--[[User:Z3254857|Begum Sonmez]] 12:42, 8 October 2009 (EST)

==Constructive Criticism of Coordinator==
--[[User:S8600021|Mark Hill]] 08:07, 8 October 2009 (EST) The following comments are general in nature in no specific order, as it would be inappropriate to suggest specific changes and then assess the final project. Comments will be added during this week and you still have one week before final submission.

* The project has improved in content and layout from the original submission date.
* A general comment about images. When you click an image and it opens, the information below the image should have an explanation of what the image shows, a reference (if from a paper) and a link to the original source (if available) as well as copyright information.
* There are still issues related to page design with large white spaces visible.
* [[:File:Mice_expressing_GFP.jpg]] What is the original source of this image? Do you have permission to reuse?
* [[:File:Genetics of laboratory rodents.jpg]] What is this transgenic mouse expression pattern showing?
* The Theiler images of embryo stages are useful to have, are they really all redrawn? I will be comparing these to the original online versions and they cannot be direct copies without permission.
* [[:File:Mouse_theiler_stage8.JPG]] Reichard's menbrane?
* Glossary still incomplete.
* Reference could be tidied up.

==Constructive Criticism of Peers==

--[[User:Z3218657|Sally Clarke]] 09:59, 1 October 2009 (EST)Well Done!

I'm just jumping straight into it..

- I Think the timeline stage is fantastic - the images and information are displayed really well

- the staging information is a little cramped and thrown in together - it doesn't flow very well and the images are all over the shop

- The history section has A LOT of information an images of the scientists, what they did and how they did it - great... i know this would have taken a lot of work but its a bit long. I think maybe making it into a timeline on different pages might help this.

- The headings and sub headings are really good and informative but there is a few formatting errors which is easy to fix

- The genetics sections is really good, nice and concise yet informative

Great assignment guys!

--[[User:Z3258567|Sando Rashed]] 09:12, 1 October 2009 (EST)hey wow lots of information in this page :D, well done with the effort use all put in it looks and sounds goood, few things im not sure if it was my computer but staging of embryonic development there was just a bunch of photos and they were crammed up and overlapping each other making it very hard to read use might want to cut down on the photos in that area or scale them down to make it easier to read. you have a lot of information in your history section its good that you have what they do and their contribution to make it look a bit better you might want to split it up into a 3 way table (name/what they do/how it helped) minimise the reading as i recall dr mark saying to much reading is not something he wants he wants something more appealing to him where he can lay in bed and mark it without falling asleep so a table would be good here. other than that its a great page :D well done hope use all do well!!

--[[User:Z3223194|Bronwyn Lewis-Jones]] 08:53, 1 October 2009 (EST) Congratulations on a great assignment. There are so many good things about this page. I think the biggest (and easiest) improvement to be made is to cut down on the amount of headings for the History and Current Research. The headings used such as "What did they do?" etc are helpful in showing the reader what exactly they are to understand from what is written, however they interrupt the flow and spread out the information so that it seems rather daunting. If you can summarise each section into a few sentences then I think that will not only reduce your contents section to a more useful size but also make the page more reader friendly. If you don't like that idea you could strike a happy medium by either having you "What did they do..." to bold instead of a heading or have (in bold or italics) a very short summary sentence under the name followed by a short few sentences. This would still give the reader an impression of what do get out of each section but would increase the flow inside and between notable researchers etc. Hope you find this helpful. :)

--[[User:Z3218146|Julianna Lam]] 01:31, 1 October 2009 (EST)
- the history section is TOO long ! the structure of the history section is good, i liked the whole idea of the sub headings ie ' what did he do?' but i think you guys included way too many people in there. the layout of the history section is not very neat and very inconsistent. you provided pictures of some people but didnt provide pictures of others. there are gaps everywhere and it just looks really messy.

- the stages and timeline parts are really good. the table looks really nice. and i especially like the pictures, very well labelled.

--[[User:Z3186093|Jenny Guy]] 18:46, 30 September 2009 (EST)

Improvements:
* The history is wayyyy too long. Seriously, there are too many sub sub sub headings. Cut it down and for each scientist make it a paragraph instead of so many dot points. I almost couldnt be bothered reading them all. Definitely not a good way to represent information. Looks as though you gave up on looking for pictures of the scientists. I would too if i had that many of them. Pick the main scientists that caused a breakthrough instead of listing all 1000 of them. Also, it is inconsistent if you did decide to keep the subsubsubsub headings as 'what he did', "what he found" and "what the importance" are generally all targeting the same question.
* I think you guys are confused as your information is conflicting. Humans have 23 pairs of chromosomes. In your introduction you state they humans and mice have the same number. However in the genetics it states that mice have 20pairs. What is true?
* There are a few gaps (large random spaces) in the genetics sections. Might want to format this a little.
* For the current research see the same massive point i mentioned first....
* Your referencing in the bibliography is inconsistent. Stick with one type of system, e.g. apa OR harvard. Some of the references aren't even referenced properly. You must reference websites.
* You haven't referenced ANY of you text. How do we know you havent just cut and paste? You need to either reference within the text (e.g. Andrews, E.A. (1895) states .....) or at the end of sentences/paragraphs with (Andrews 1895) or the number used in the bibliography.

--[[User:Z3255007|Sadaf Masood]] 15:43, 30 September 2009 (EST)Hey Group 4! Congrats on your great project guys! I have listed few points that might help:

1. Very well researched History section, lots of people doin lots of work..maybe you can make it a little short as its just a little too much info on them.

2. A bit more proper formatting, lots of gaps after every picture and table, maybe you can get rid of them

3. Timeline is great, just enough info to make sense and needed.

4. 'Why use of mouse is important?' this issue is well discussed. Great work!

5. Impressive hand drawn diagrams, any chances of making them a little larger on the main page? it would look really good!

6. Glossary is also needed...will make our life easier is understanding few words.

Rest is all well guys. The current research Section is awesome, very informative and lots of details. Its a great project guys...Best of Luck!!

--[[User:Z3218792|Gabriela Pinget]] 12:59, 30 September 2009 (EST) Hello! constructive criticism as follows:

- intro is a nice ease in but needs to be edited for grammar

- wow the history section is very well researched. I like that you've included so many contributors but are you sure you need to go into so much detail? It looks a little cluttered and detracts from the overall purpose of the assignment. Think about cutting down on it a little

- I really like the ''staging of embryonic development'' section! very engaging and well formatted! well done

-I also liked the timeline of development. I like that there was not too much information at each stage, but just enough to give a clear outline. Maybe a link to find out more would be useful

- genetics section is perfect

- again, the current research section is a little too spread out. The continuous "what did they do..." works well to begin with but after a while gets to be too much

Overall, a really nice looking page

--[[User:Z3295026|Joe Nassif]] 17:59, 29 September 2009 (EST)

Awesome looking wiki page, mouse group 4 an excellent assignment.

It is a really interesting reading and viewing your wiki page the content flow really well when reviewed.

1. The assignment is impressive it outlines the point with the use of sub headings which is always useful in the project as a referencing point.

2. (What did he do?) and (What did they find?) is a great way to state the history as it allows the reader to quickly get the brief information and understand it , also the illustrations throughout the assessment was great it referred to the text really well, which supported the info impressively. The hand drawn images in the (staging) and (timeline) sections were extremely great the detail was impressive.

3. Some ways to improve the assignment:
A) There are some unnecessary data throughout the project which are not relevant for example the ‘length of mouse embryo’ , removing this sections can truncate the assignment which would enhance the structure.

B) Current research information on the background of the research finders reveal great info on the development of the model usage, the findings and the relevance to human embryology have been summarized greatly.

C) The referencing need to be fixed in proper format. Visit : www.lc.unsw.edu.au/onlib/ref_apa.html for help with APA referencing

D) a glossary is needed to help the reader understand terms.

Overall a great project. The criteria was covered really well it, stated specfic topic in regards to the mouse and it embryonic developent which group 4 has summarised really well.

--[[User:Z3295026|Joe Nassif]] 17:59, 29 September 2009 (EST)

--[[User:Z3217015|Mitchell Mathieson]] 09:39, 25 September 2009 (EST)Page looks good. I liked how there was heaps of information on the genetics and the current research (however, this was a bit too spread out maybe). There seems to be a lot of gaps in the text, so the formatting could be maybe tightened up. The references maybe should be formatted better, and there is repeated information (tables and text for stages), but I really like how clicking the image goes to another page with more information...that is cool. The drawings are cute as well. Overall very good, I think formatting was the downfall from that, but the information is top notch.

--[[User:Z3126328|Jin Lee]] 16:42, 26 September 2009 (EST) hellow group4~ very impressive assignment guys!well done! I really enjoyed reading your assignment. it was easy to read and the information was relevant. However, I found the formatting of the images and texts were too sqeezy. may be resize the images and line up with the relevant information. Also, I think the reference needs to be looked after as well. Overall, the contents of the assignment is very useful and interesting.

--[[User:Z3187802|Vishnnu Shanmugam]] 20:02, 26 September 2009 (EST)Congratulations mouse group on an excellent assignment. It is a real joy to read. One of the best features of the assignment is how it gets straight to the point with the use of sub headings “What did he do?” & “What did they find?”. Even the images used throughout the text are interesting, especially the fully labeled hand drawn images in the “staging” and “timeline” sections. Some ways to improve the assignment:

-There are some unnecessary graphs in the assignment such as “the average length of mouse embryo”, “number of cells” and “number of somites”. These could perhaps be combined into a single graph. It will also reduce the congested appearance of the assignment as it seems too densely packed with no particular focus.

- In current research section, it is advisable to reduce the number of research and focus on just a few but provide more comprehensive information on the background of the research, the findings and the relevance to human embryology. It currently contains too many different types of research that have described very briefly.

- Edit the "content" section at the top of the page as it's length seems to be getting out of control. It is perhaps better to exclude the sub headings “What did he do?” & “What did they find?” in the contents.

- The referencing in the text need to be completed as there are some sections well referenced and others with no referencing. see www.lc.unsw.edu.au/onlib/ref_apa.html for help with APA referencing

- A Glossary would also complement the text.

Overall a classy project, only some changes necessary

--[[User:Z3126345|Gang Liu]] 16:49, 27 September 2009 (EST)This is one of the better wikipage i have seen so far. It demonstrates not only extended literature research skill, but also an in-depth understanding of the topic. The content of this page has been consistent throughout. In addition, paragraphs are straigtforward and concise, and make the point. Detailed texts with accessory graphics are appropriate in here. In paticular, history section. It describes the model use in terms of details of experiment, and results of experiment. Stages and timeline are very self-explanatory and visually enhanced.

This project can be improved by considering the following points.

*Lack of glossary list. Need to provide meaning of words such as "polyestrous", "oocyte", "Ectoderm", "endoderm", etc;

*Reformat stages section. I found this section a bit "busy". Might considering resize the pictures.

Last few words. I have learnt from this page that mouse has the same size genome as the human genome; Mouse genes can be easily manipulated and studied; Mouse a high degree of homogeny with humans. Well done!

--[[User:Z3217686|Thomas Dangerfield]] 14:12, 28 September 2009 (EST)Hey guys! Wow so much info first off! Not entirely sure we need to know about everyone involved in the history, maybe could have collaborated and joined people together or possibly even left certain people out. To me, the whole page is like how mark described, with everything all one great smudge of info with no real formatting or sequence or continuation. It was just kind of like an overload and reading it was a little difficult at some stages. Also corresponding the images in the timeline could have been included in the text.

Also I think your numbering of figures is a little off in the timeline section, with figures 1-4 on the right and then you have figures 4-7 describing stages 12-14. Just seems that there is two figure 4's for two different images.

Love the large amount of research and information, but could just work on your presentation and you'll do fine! Great work guys!

--[[User:Z3185685|Sumaiya Rahman]] 16:56, 28 September 2009 (EST) Hey guys! Overall a very nice assignment with a great deal of information! You can tell you guys did a lot of research. The contents are massive! Maybe you could cut this down and not use so many subheadings such as “what did they do?”, “what did they find?” and only have a subheading for each researcher. The introduction is well written. The history of model use has some really good information. My only criticism in this section is that there are a lot of gaps and blank spaces. You just need to delete all the spaces. The staging section showed a lot of research and effort. Well done!! The only thing is, is it a bit too much? There are a lot of tables and images that it was hard to keep track. Maybe this could be set out differently and made to look less busy. The timeline of development is fantastic and set out really well. It is very easy to understand and the drawings are great! Once again the current research is very spread out with lots of spaces. Also adding a glossary may help the readers in understanding the text. GREAT JOB!

--[[User:Z3215682|Carly Mooney]] 11:49, 29 September 2009 (EST)
I think all your material is there but the page layout needs work. Especially the history of the models use.
*The spacing and images are inconsistent. I liked the history of timeline section information and how it was presented, just the spacing of it all needs to be even.
*The stages of embryonic development was a little all over the place, and very daunting to look at.
*A glossary would help.
I think you guys did a really good job and just have to work on presentation.

--[[User:Z3220040|Joanne Raffel]] 16:14, 29 September 2009 (EST) Very impressive page, however it was very long!!! The introduction was very clear and concise. The history section was extremely long and poorly formatted, there were too many pictures with too little information, I would recommend cutting some of the images and just keeping the pictures of those who made a significant impact upon the mouse embryo, I also thought it was unneccessary to write after each subheading, what did he do and their result, I would prefer if it was just one paragraph. Your main heading were overshadowed by the subheadings and the rest of the text. There is a lot of information for the staging section, which is good however it can made it difficult to read, I would recommend having some of the information linked onto a separate page. The picture and format for the timeline section was exceptional however it lacked information, I also thought that it was irrelevent rewriting the timeline after the pictures, I would recommend including it with the picture rather than after it and the graph size made it seem insignificant. The genetics section was very extensive and I thought some of the information was better included with the current research. Similar to the history section, I thought the formatting of the current research section was very unorganised and too spaced out. Overall a very nice page.

----

--[[User:S8600021|Mark Hill]] 01:46, 8 September 2009 (EST) Well the content is there now, but what a mess, and I am not just talking about the formatting problem which can be easily fixed, you have no structure to your project, its not a matter of throwing everything at a wall and seeing what sticks. Work together for an integrated coverage. Timeline of development, is not the way to start your page with a huge table of data.

--[[User:S8600021|Mark Hill]] 08:43, 21 August 2009 (EST) OK guys, time to see some actual content uploaded on both your discussion and project pages.

* Timeline of Development - how long (Emily)
* Staging - are there species specific staging, what occurs when (Elide)
* History of Model Use - when was it first used, what embryology research (Begum)
* Genetics - chromosome number, sequencing (Angama)
* Current Embryology Research - research papers and findings (All)

Here is a link for timeline
[http://books.google.com.au/books?id=XLIarRWHikAC&pg=PT199&lpg=PT199&dq=mouse+embryo+development+timeline&source=bl&ots=fobLBRiacx&sig=cK4cuZah6Ksczs3o8v4NXQqoAyk&hl=en&ei=rGB6SvTHMMmIkAXB_piAAw&sa=X&oi=book_result&ct=result&resnum=3#v=onepage&q=&f=false
]

link for the mouse brain development timeline http://en.wikipedia.org/wiki/Mouse_brain_development_timeline

hey guys there is another interesting link about mouse development http://mouseatlas.caltech.edu/index_content.html

Hey Emily. The link below has a timeline that you can check out in your spare time. Begum.
[http://books.google.com.au/books?id=4juoa5xMs8oC&pg=PA31&lpg=PA31&dq=mouse+embryology&source=bl&ots=9tJAfRG4R6&sig=hjR5Zs-sL1sCW5FY8FnR5TMaUk0&hl=en&ei=LuuMSr_aCNjakAX714icDA&sa=X&oi=book_result&ct=result&resnum=9#v=onepage&q=mouse%20embryology&f=false]

Hi girls,
here is a link to a text book about mouse embryology it looks pretty good. hope it can help
[http://books.google.com.au/books?id=4juoa5xMs8oC&printsec=frontcover&dq=mouse+development&source=gbs_similarbooks_r&cad=2#v=onepage&q=mouse%20development&f=false]
let me know if the link doesnt work. Ive been working on the main page, so have a look and tell me what you think, Also what are we doing about references? If we have used information but put it in our own words do we need to put in text citations,or do we just reference the journal at the end? I just want to be very careful. Thanks!

Hey Elide, i think your work is looking really good. its very easy to read and understand. keep going!!!! emily

hey everyone,
I have uploaded some of my timeline work. I'm not sure if I've gone into to much detail or not and also on how is best to present the timeline. It is fairly basic and definately needs some work - especially on presentation, grammar, etc. let me know what you think.
Emily

good site for stages or timeline- atlas of pictures of stages- The Edinburgh Mouse Atlas Project [http://genex.hgu.mrc.ac.uk/]

Hello girls, it's Begum. I put some info under the history section. Wanted to let you all know that I've got a fair bit of info, and I will do my part as best as I can. Btw Emily, I think maybe dot from would be best for you, but if you can use those lines that I was talking to you about on Wednesday, that would be great...I know it's hard.

hey everyone, i have put some info under the genetics heading and some under research. I am still struggling to find the appropriate info related to the topic of genetics because there is alot of info abt the different types of stains used in labarotories but not the genetics. I emailed Dr.Hill and have asked him what to include in my section specifically,hopefully he will help. So far i have just started it needs alot of more work to be done,girls just read thru my section n leme know wt u think of it. have a nice weekend everyone. Angama.

Hi girls!
Begum, you history info is really good. If very interesting! I really like how you are doing it in order of dates of discovery and what they did, what they found etc! Cant wait to know more.
Angama, your doing well! it sounds like your finding the info hard to get. I'll keep an eye out for you! If your stuck on what you sound be doing then i might have a few ideas. I remember Mark Hill saying that you should compare the genome to the humans genome. so maybe if the genome is the same size as the humans, could you descibe similarities or differences? I know that there is a link to the mouse genome on the mouse web page he gave us ( next to the discussion link). Are you just ment to list the mouse genome sequence? could you go into what genes code what, eg which one codes for the sex linked gene, is it the X and Y gene etc? hopefully Mark gives you some ideas.
well as you might have noticed i've been adding to my stages. the only thing is im worried about there being too much info up there. basically ive tried to get all the info available included in my stages to make sure i cover everything, and then later i'll go over it all and edit and polish it up a bit. Ive done some drawings to the best of my ability, but i can scrap them if you all think they arnt professional enough. just thought i'd try to present the information differently. let me know if you think i'm including too much information. i think i'm having the same problem as you begum, there is lots of info! Elide

Thanks Elide. I'm trying. (Again, loved the artwork!)Btw, Emily, I had a think about your section and I think it might be too much 'clicking' back-and-forth if we link the displayed pic to the 'info' page. Don't stress, you've got the info (heaps which is excellent) but make sure you get some pictures soon so we can start drawing (I'm helping with the drawings as well ok). Mark said 'Nature' and 'Science' have useable images so lets make that our start.
BTW, I will be using the question mark symbol(???) so I don't forget to reference. Begum

Hey everyone, I have found an online text book. it has a chapter on genetics and history and a lot of other stuff. [http://books.google.com.au/books?id=Vt6nUmz1yEQC&pg=RA1-PA207&dq=mouse+development+anatomy&client=firefox-a#v=onepage&q=mouse%20development%20anatomy&f=false] Emily

Hey girls. If you've seen my section, the info is not on the main page, but linked to another page. I thought that it might make everything look more neat. I thought we could all do it like that. It's just an idea. Something different. Maybe we could have something on the main page (picture of a mouse). Your thoughts everybody? Begum

hey begum, ur work looks really good. i like the idea of linking the work to another page. - we don't have to worry about to much info being on the front page and it gives people to option of viewing the work if they want to. ive been working on drawings, i'll show them to you next week but am not sure how to upload them at the moment. Emily

Thanks! That sounds great that you like the idea. About the photos that you are drawing, if there by hand, you can scan them somehow. But overall,
1. click 'Upload File' on the left hand side of this page
2. New page comes up: click 'Browse' and choose your file that you want to upload.
3. Name it (under the Browse button)
NOTE: write down what you named the file as because like Elide says "...it's going to be lost in space!..."
4. Write down info/comments (like who is the author (YOU), and if the drawing is based on a picture)
5. UPLOAD!
6. Go to your section and just normally type this down to the area you want the picture to be seen:
[[image:THE NAME THAT YOU SAVED THE FILE UNDER.jpg|thumb|200px|right|WHAT YOU WANT THE FILE NAME TO VISUALLY COME UP AS]]

Your thoughts Angama and Elide? (about the linking of our sections to separate pages?) Begum.

Oh and another thing:
What do you girls think about my page, I've got a heading for each DATE and underneath each there are further subheadings (e.g. 'What did he do?'. Should I change them to just text, I mean, does it look messy with sub-sub-headings? Begum.

wow girls! great work.. okay so i asked mark about a new page and he said to avoid it because our info is meant to be on our one page. he said if there is extra information on what we wanted to say but is too much for the main page then have a link to our discussion page. (which is what im going to do) Begum your new page is fantastic!! you have done lots of work! but why dont you just put it on our main page? also girls i think we are getting too carried away with info. just keep it simple! i'm sorry i havent been around this week to work on it but i plan to get going asap. just fixing up some things, summarising, writing introductions etc.
did you all read his note about slabbing info onto our page?? how about some introductions, and sentences to ease ourselves into the content. planning on trying to work on that now anyway..

also lets get the information flowing. why dont we go intro, history of model use, stages, timeline, genetics, then current use.. what do you all think?

hey, i thing that that sounds like a good, logical way to do the page. i've finished the drawings, just need to upload them. About the timeline information, is there anything specific that i should include. the stuff that is on the page is a little vague and so i need some advice as to what are key points that i should include. i know that the drawing are very simplistic, let me know wjat you think about them. ive put one up below. i just need a way to link it to text. emily

Thanks Elide. You know, I think that's a great idea. Have it all on one page, seems less 'diverging...', seems more COMPLETE. I love the ORDER as well. I'll fix all that up!

Hey girls, please have a look at what i've done on the timeline. the images are all hand drawn based upon the text: 'the house mouse'. if anyone could give me any ideas on how best to present the pictures - which would be better - next to or below the text? keep in mind that it is incomplete and there is an illustration for each day of development (i.e. 19 in total). if you think that is too many let me know, some may be similar to Elide's ones. Also, do you think i should put some colour into the drawings? Emily

I love your work Emily. All you need to do is put the info on the growth of the mouse that is on the main page, onto the page with the graph of the growth of the mouse embryo...we talked about that before any way-AND I think your parts finished! Begum.
Angama, I added something to the end of your section that I thought was interesting. Have a look. And are you mentioning manipulation and 'shut-down' of the genes in your section?? Begum.
To everyone, apparently ''Mus Musculus'' is the scientific name of the common house mouse, not the mouse. I was thinking of editing that.

HEY EVERYONE! well i've added in some pictures just to make it look more visual, change them if you have better ones.. and i'm going to be working on the current research section tommorow. oh i also added some graphs like we thought of for emilys section.. so i think my section is finished finally! what do you think? can i just say, I think the whole thing looks great! you girls have been a pleasure to work with! :) Thanks so much!!

hi girls, i am sorry..i have been very busy during the mid-sem break and i know we all had our exams and assignments due. but i was having some issues in my family and also the exams and assignments so didnt really had the chance to read wat u girls have got on the main page. i just finished reading thru it and it looks amazing..WELL DONE GIRLS!! you all have done a marvellous job...Eldie and Begum thanks for suggesting some main points to add for the genetics.i am currently working on it.. hopefully tonight i will have all the information on the page..Begum i love how you have presented alot of info into a very easy and understandable way..it makes so much sense..n it looks very nice with the pictures. Eldie and Emily great amount of work and the pictures and the graphs are superb. i just had a look to other groups pages. n i think so far our page looks very interesting with concise info n amazing pictures. n Begum yes i read what you have added thanks for tht..i will cu girls around..gudluck everyone. cheers. Angama.

Girls can you please help me out.. i am so annoyed..
like rite now i was typing some info and when i clicked to save.
it says "conflict" so i think some one else is also editing
the page at the same time that i am. and i lost all my work..arghh..
so which means i have to type it all again.
is there any other way that it tells me that someone else
is also using it so i dont click on save or even preview
because when i do tht i lost all the work tht i had.
If anyone knows please let me know. thanks. Angama.

Current research : I have put some information in the current research part. not sure where they should be put. Begum, as discussed you can edit it or place it in its appropriate place.

Don't stress Angama at all, now you know, it will be over soon. Uploading it easy:

1. click 'Upload File' on the left hand side of this page

2. New page comes up: click 'Browse' and choose your file that you want to upload.

3. Name it (under the Browse button) NOTE: write down what you named the file as because like Elide says "...it's going to be lost in space!..."

4. Write down info/comments (like who is the author (YOU), and if the drawing is based on a picture)

5. UPLOAD! 6. Go to your section and just normally type this down to the area you want the picture to be seen:

It's easier than it is typed! Of you still have problems I will be at the embryo lab, of there is exams there the ANAT LAB opposite to it, if not Level 3 library computers.

[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19538749| maternal diabetes alters transcriptional programs in the developing embryo], [http://www.ncbi.nlm.nih.gov/pubmed/19414407?ordinalpos=35&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum|Abnormal mammary gland development in MMTV-CBLC transgenic mouse], [http://www.ncbi.nlm.nih.gov/pubmed/19394325?ordinalpos=40&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum|Sonic hedgehog signalling inhibits palatogenesis and arrests tooth development in a mouse model of the nevoid basal cell carcinoma syndrome.], [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=55&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum| Fibroblast growth factor 18 gives growth and directional cues to airway cartilage.]

Hi girls, i think i have completed my section. could you all please just read thru it and leme know wat you think of it. i did it to the best of my ability. Hopefully you will all like it if you girls think therez anything more to add or to delete leme know..thanks. gudluck girls. Angama.

Angama your work is fantastic! Thanks so much! im sorry i wasnt around to help you with the problems. hope it went okay. your info is perfect! im very happy with our page! lets hope everyone else is :)

I love it Angama, good work! And the pictures you uploaded are very interesting. Cool. Awesome. Your done!! Begum.

Thanks Begum :) Girls gudluck and cu all tomorrow. Angama.

== Discussion after peer assessment and constructive criticism ==

Hi girls,
Ive started making some changes to the page based on the comments recieved.
Note i've also started a glossary of terms. Also many of our comments regarded our references,so It would be great if we could all reference the same, lets say APA because this is the most common way for referencing. I have gone through our references and tried to format them in APA. many are incomplete references so i have bolded the references that are missing detail. please if you all could complete your references that you added to the list. Also shall we number the references so we can include the numbers in the text as in text references? like foot note? what do you all think... there have been many comments on our current research page.. so how would you all like to fix it? I personally think its way too much. It seems to have accumulated heaps of info from when I last saw it. Is there anyway of summarising the current research info to focus more on how they are used rather than the institute and scientists involved. I think the most important info in this section is what mice are being used to discover currently and proof of the year of study. Cant wait to hear what you all think! Elide

one more thing.. ive tried to edit the contents, as one of our peers suggested, however i cant seem to edit it. do any of you know how to do this?
Elide

hey emily, i see you have reduced the heading in the contents!! thats great! i was just thinking that maybe we dont need so many headings in those 2 sections at all. what do you think about just making all the scientists and the names of people/ labs just in bold.?

Hi girls, have a look at the changes i have made to my section. let me know what you think. Emily

looks good!!
also girls could you please add words from your sections to the glossary, as that whole list is only from the staging section. thanks. elide

Hello girls. I will be re-formatting the history section in order to get rid of the 'gaps' that my peers have mentioned. Also, Elide mentioned yesterday that placing all the 'History' pictures towards the right-side of the page would look more neat, as well as add to the flow of the page. I think this is a great idea. Begum. Oh, and '''what do you guys think about taking out some information (findings)?''' Some students have mentioned that there is too much information/researchers.
And Elide, I'm might change the names of the researchers. like you said before, to bolded text. It would look much more neat. I might, also, '''apply this to the Genetics section. What do you all think?'''

'''Begum's Problem'''
Hey. I placed all pictures to the right-hand side (history section), but the pictures don't correspond well with the text. Any suggestions?? Should I than put the towards the left? Love the change to the timeline section Emily.

HEY BEGUM!!
so your problem.. I dont think the pictures need to match up because if they have a title of the person then the reader can find their picture. plus the comments are on the spaces and gaps between text, not the pictures.. so maybe just put them all underneath each other and even if they dont match up then at least the writing looks more organised. try making the images 200px and not so large and it could work better?. also the bit about taking out the headings in the genetics would be great!! bold would still look fine! goodluck! xox

--[[User:Z3254857|Begum Sonmez]] 14:54, 10 October 2009 (EST) '''TO ELIDE''': I was going to change the headings 'Reproduction' and 'Theiler Stages' under STAGES to bolded text. What do you think? Plus, like you said before, I'm on that ref. list, I will summarise the current research, and change those headings. If the HISTORY pictures match up to the the text, it would be more convenient for the viewer, don't you all think so??? However, the text would appear better the other way with the images al together on the right. Yes, I'll do that.

Hey '''Begum'''!
yes what a great idea about changing the headings in the staging section! the whole page needs to have the same structure throughout! I shall change them right now! :) i'm a little confused about the bit you said about what you said about the ref list. do you mean that you will fix yours? ive been through some of them and looked up the missing details. some are lacking their full reference though. but that would be so great if you could fix up your references. i think the ones in bold are the ones still needing work, but correct the others if you think they arent finished.
well i think the history section looks great! even though the pictures dont match up, they are still there and they look neat and have the same format as the rest of the page. and even better there are no spaces! so it looks great!! i wouldnt worry too much, you've done a such great job providing detail, the pictures are just a bonus!
the reference list looks great! thanks for your help! xox Elide

--[[User:Z3254857|Begum Sonmez]] 20:55, 11 October 2009 (EST)Hello girls! One more thing left: Current Research section. One student said to reduce the number of 'research', but include more information on each. I don't think adding more info under the research is necessary. But '''just keeping the 'breakthroughs'''' would be good, the more important ones. What do you all think? Also, '''what should the headings be''', any suggestion? Should I keep the Organisations as the headings, or the names of the researchers involoved, and/or the dates?

--[[User:Z3224449|Elide Newton]] 11:41, 12 October 2009 (EST) hey. about the current research section. well now that it doesnt have as many spaces and gaps it doesnt look as long, so maybe thats why the student saids to reduce the number of examples. so i'm with you begum, keep the important ones. for example if there are 2 examples of its use in cancer then have only one cancer example. yes headings . i think maybe keep the organisation and date. see what the other girls think.. i'll have a think about it too, and see what we can improve on that section.. overall are we all happy with how its looking? i think its looking great! even the reference list doesnt look messy! :)

--[[User:Z3224449|Elide Newton]] 14:48, 13 October 2009 (EST) Begum! your work is amazing! the current research section looks so much better! I think the page is starting to come together now! what i plan on doing is giving the whole thing a good proof read to make sure the flow, format, text, and info is consistent throughout. what else should we do with it. is everyone liking the improvments so far? dont forget we only have tomorrow to work on it!

--[[User:Z3254857|Begum Sonmez]] 19:43, 13 October 2009 (EST)
Thanks Elide!! I have and will continue proof reading the history and current research section (for any mistakes and grammar issues), so you don't need to proof read those sections in-depth (save you time). Just to let you all know, I may or may not get rid of some current research findings. I think we all did a great job, and our page looks very organised and professional. Well done to all of us.

== List of things still to do ==
* proof read the whole thing
* check if your images have info underneath, reference and copyright liscence (Angama you might need to check your genetics pictures.) If your busy I can do them for you but i need to know the reference and copyright permission. Elide

== Changes made ==
--[[User:Z3224449|Elide Newton]] 12:17, 2 October 2009 (EST)
*Removed table of stages from discussion page
*Corrected introduction " the mouse has a similar genome to the human"
*In stages section changed size of images to 200px and moved to the right
*Removed spaces and gaps from stages
*Formated stages section to look neater
*Deleted the links to tables on discussion page
*Added in table of theiler stages 12-14 which was on the discussion page
*Started a glossary of terms
--[[User:Z3224449|Elide Newton]] 16:17, 5 October 2009 (EST)
*Added in text citations to the staging section
*Added in more definitions for glossary of terms and referenced glossary
*Went through each reference of reference list and changed the format it into APA, bold for incomplete references.. to note that it needs to be fixed.

--[[User:Z3252340|Emily Wong]] 11:28, 6 October 2009 (EST)
* Edited the contents so that it wasn't as long i.e. took out all the repeated "what did he do?" etcs.
* Edited current research so that contents are not as long. Again taking out the "what did the do" etcs.
--[[User:Z3252340|Emily Wong]] 15:38, 8 October 2009 (EST)
* Edited the timeline of development section by:
** Taking out the written text and incorporated it into the captions below each drawing.
** Rearranging the work so that it was in a better position
** Linked the graph 'Average length of the mouse embryo' into the section by writing a small blurb on it.

--[[User:Z3224449|Elide Newton]] 10:44, 9 October 2009 (EST)
* Removed spaces in sections current research and genetics
* Moved images to the right and changed size to 200px in current research section
* re-uploaded theiler stage 8 image with typo fixed ( reichards to Reicherts)
* added information below images in the staging section.
* added links to source below images in staging section
* deleted 'Photo of mouse vascular development at Theiler stage 20' because I am unable to find copyright liscence
* went through each ref and chagned to APA, had to look up dates and authors for incomplete references added by other students. still some are not complete (in bold) so if you added these references could you please fix.

--[[User:Z3254857|Begum Sonmez]] 12:28, 9 October 2009 (EST)
*Changed the heading 'Chromosome number and banding patterns' under Genetics, from being a main heading to a sub-heading. This was a small mistake that had to be fixed.
*Changed the sub-headings of the history section, that list the years, to bolded text. The reason for this change is that it condensed the amount of headings in the 'Contents', allowing the viewer to have an outline of the page instead of a massive list of each heading. As a result, the page looks more neat, and each section is consistent with eachother.
*Placed all pictures in the History section to the right-side of the page. This is more consistent with the rest of the page, and adds to the flow of the page.
*Placed 2 spaces between each finding, and 1 space between each part of the finding (For example, 'What did they find', 'The Importance'). Again, this is another feature which adds to the consistancy of the page. Many of our peers pointed out that our page was messy. This change helps to solve the problem.

--[[User:Z3224449|Elide Newton]] 20:38, 9 October 2009 (EST)
*Removed headings from current research section and made them bold.
*Finished the glossary of terms from the staging section
*worked on current research. (removed spaces, formated, removed lists of names and added 'et al')

--[[User:Z3254857|Begum Sonmez]] 14:45, 10 October 2009 (EST)
*Changed the sub-headings under the Genetics section to bolded text. There were no complaints about this from our peers. However, since this was applied to the History section, applying it to the Genetics section would be consistent and more neat.
*Placed all HISTORY pictures beneath one another in order to be consistent with the arrangement of other pictures throughout the page.
*Deleted some of the headings (what did they, how did they...) under the history section, as the contents of some of the headings were related. One student mentioned this. As a result, there is less headings, and a greater degree of clarity.
*Edited the Reference list by dividing it into 2 headings ('Books and Articles' and 'Webpage'), and converted some more references into APA style. Just one more conversion left.
*Added the definitions of 'Allophenic', 'Chimera', 'Corpus luteum', 'Somatic tissue' and 'Stem Cell' to the Glossary List.

--[[User:Z3224449|Elide Newton]] 19:44, 10 October 2009 (EST)
*Removed headings from staging section and made bold instead to be the same as the whole page
*Removed two gaps from the genetics section

--[[User:Z3254857|Begum Sonmez]] 14:24, 12 October 2009 (EST)
*Changed some of the Sub-headings under the Current Research section to make it more consistent throughout this section.
*Converted the information under each finding under the Current Research section into numerous small paragraphs because one student outlined that the use of the sub-sub-headings were good at first, but it than became overwhelming. This change enhanced the layout without using the sub-sub-headings and without ending up with a slab of text.

--[[User:Z3254857|Begum Sonmez]] 11:18, 13 October 2009 (EST)
*Changes the heading 'THE MOUSE' from all upper-case to lower-case. This is consistent with the other main headings.

--[[User:Z3252231|Angama Yaquobi]] 19:35, 13 October 2009 (EST)
*Removed some of the images in the genetics section because there was not much information about the image.
*Replaced those images with new images containing information about the image.
*Added the definition of 'Haploid', 'Mutation', 'Oncogenic', 'Renaturation', 'Telocentric', 'Transgenic', and 'Transposition'.

2009 Group Project 4

2009-10-13T08:42:29Z

Z3254857: /* Introduction */

== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Is a small organism which can be easily maintained
*Is not expensive
----

===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:Wesley_Whitten.jpg|thumb|200px|right|Wesley K. Whitten]]
[[image:Dame_Anne_Laura_Dorinthea_McLaren.jpg|thumb|200px|right|Dame Anne Laura Dorinthea McLaren]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Beatrice_Mintz.jpg|thumb|200px|right|Beatrice Mintz]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]
[[image:Teruhiko_Wakayama.jpg|thumb|200px|right|Teruhiko Wakayama]]
[[image:Leroy_Stevens.jpg|thumb|200px|right|Leroy Stevens]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Gingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development so far a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development clink the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm.
{{Insert timeline}}
----
===Genetics===
[[image:2greenpupm.jpg|thumb|300px|right|Transgenic mouse pup]]

'''Genome'''

Sequencing of the mouse genome was completed in late 2002. Tha haploid genome is about 3 billion long (3000 Mb distributed over 20 chromosomes) and therefore equal to the size of the human genome. The current estimated gene count is 23,786 and humans are estimated to have 23,686 genes.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino.
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).
[[image:Nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome. Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.
[[image:5chris6m.jpg|thumb|300px|right|Conditional Gene Expression]]
Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function. However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

[[image:Figure3-3.jpg‎|thumb|200px|right|Examples of some commonly used mouse strains]]
[[image:Transgenicmouse.jpg|thumb|200px|right|Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition]]
Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]
[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve in mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===
[[image:NIDCR.jpg|thumb|200px|right|Members of NIDCR]]

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the in organising the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:
1.Supports the multiplication of the H9 cells better than the 3T3 line.
2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: ''An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells''. Link to Abstract [http://www.library.unsw.edu.au/cgi-bin/Data/db.cgi?db=fulltexttest&uid=default&view_records=1&url=http://gateway.proquest.com/openurl?atitle=Harvard+University,+School+of+Medicine;+Human+embryonic+stem+cells+propagated+on+immortalized+drug-resistant+cell+line&date=2006&rft_val_fmt=ori:fmt:kev:mtx:journal&spage=236&issn=1551-529X&ctx_ver=Z39.88-2003&genre=article&res_id=xri:pqd&req_dat=xri:pqil:pq_clntid=&Address=http://gateway.proqu] or [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155) - an Alox5-deficient mouse on a B6 background, and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on mormal HSCs.

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy will be clinically trialed in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia, et al. used the knock out mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knouck out mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cell differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ here].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in critical developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. used the mouse as a model organism to study the epithelial - mesenchymal crosstalk that occurs in Wolffian duct and testis cord development. They found that the epithelial-mesenchymal interactions in the development of these two male structures are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins when mutated become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin rather than the bacterial cell numbers is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab on the mice containing EGFR mutated lung tumors.

It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''' which has been studied to assist in generating antibody and CD4 T helper cell responses.

This process, explained above, was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Haploid:''' A set of chromosomes containing only one member of each chromosome pair. The sperm and egg are haploid.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Mutation:''' is a randomly derived change to the nucleotide sequence of the genetic material of an organism.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Oncogenic:''' An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Renaturation:''' The process by which proteins or complementary strands of nucleic acids reform their native conformations.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Telocentric:''' a chromosome like a straight rod with the centromere in terminal position.

'''Transgenic:'''A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered using genetic engineering techniques.

'''Transposition:''' is a kind of mutation in which a chromosomal segment is transfered to a new position on the same or another chromosome.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

{{Template:Projects09}}
[[Category:Mouse]]

Talk:2009 Group Project 4

2009-10-13T00:18:42Z

Z3254857: /* Changes made */

== Project Updates ==
--[[User:Z3283499|Antonio Lee]] 10:57, 2 October 2009 (EST) Hi everyone, I will be working with you during the Lab10 Tutorial and here is the news link and PDF of the manuscript for your group exercise. I encourage you to read the paper before the tutorial. Also, please indicate next to the questions below (using either your initials or student number) which one of the four questions you wish to address.
:'''Group 4 :''' [http://www.scientificamerican.com/article.cfm?id=stem-cells-from-fat-cells '''Induced Pluripotent Stem Cells Created from Fat Cells'''] in Scientific American Published online 8 September 2009 [[Media:ANAT2341_Lab10_2009_Group 4 Reading.pdf|Manuscript (PDF): Feeder-free derivation of induced pluripotent stem cells from adult human adipose stem cells]]

:Question 1. What is the background to the existing problem / disease condition?--[[User:Z3252340|Emily Wong]] 13:41, 8 October 2009 (EST)
:Question 2. What approach / method did the research team take to tackle / improve the problem? --[[User:Z3252231|Angama Yaquobi]] 19:27, 7 October 2009 (EST)(Angama Yaquobi)
:Question 3. What was the breakthrough / major advancement OR failure / drawback? and why might this be of significance?--[[User:Z3224449|Elide Newton]] 13:43, 8 October 2009 (EST)
:Question 4. What are the next steps in moving forward? What are the next or new hurdles to overcome?--[[User:Z3254857|Begum Sonmez]] 12:42, 8 October 2009 (EST)

==Constructive Criticism of Coordinator==
--[[User:S8600021|Mark Hill]] 08:07, 8 October 2009 (EST) The following comments are general in nature in no specific order, as it would be inappropriate to suggest specific changes and then assess the final project. Comments will be added during this week and you still have one week before final submission.

* The project has improved in content and layout from the original submission date.
* A general comment about images. When you click an image and it opens, the information below the image should have an explanation of what the image shows, a reference (if from a paper) and a link to the original source (if available) as well as copyright information.
* There are still issues related to page design with large white spaces visible.
* [[:File:Mice_expressing_GFP.jpg]] What is the original source of this image? Do you have permission to reuse?
* [[:File:Genetics of laboratory rodents.jpg]] What is this transgenic mouse expression pattern showing?
* The Theiler images of embryo stages are useful to have, are they really all redrawn? I will be comparing these to the original online versions and they cannot be direct copies without permission.
* [[:File:Mouse_theiler_stage8.JPG]] Reichard's menbrane?
* Glossary still incomplete.
* Reference could be tidied up.

==Constructive Criticism of Peers==

--[[User:Z3218657|Sally Clarke]] 09:59, 1 October 2009 (EST)Well Done!

I'm just jumping straight into it..

- I Think the timeline stage is fantastic - the images and information are displayed really well

- the staging information is a little cramped and thrown in together - it doesn't flow very well and the images are all over the shop

- The history section has A LOT of information an images of the scientists, what they did and how they did it - great... i know this would have taken a lot of work but its a bit long. I think maybe making it into a timeline on different pages might help this.

- The headings and sub headings are really good and informative but there is a few formatting errors which is easy to fix

- The genetics sections is really good, nice and concise yet informative

Great assignment guys!

--[[User:Z3258567|Sando Rashed]] 09:12, 1 October 2009 (EST)hey wow lots of information in this page :D, well done with the effort use all put in it looks and sounds goood, few things im not sure if it was my computer but staging of embryonic development there was just a bunch of photos and they were crammed up and overlapping each other making it very hard to read use might want to cut down on the photos in that area or scale them down to make it easier to read. you have a lot of information in your history section its good that you have what they do and their contribution to make it look a bit better you might want to split it up into a 3 way table (name/what they do/how it helped) minimise the reading as i recall dr mark saying to much reading is not something he wants he wants something more appealing to him where he can lay in bed and mark it without falling asleep so a table would be good here. other than that its a great page :D well done hope use all do well!!

--[[User:Z3223194|Bronwyn Lewis-Jones]] 08:53, 1 October 2009 (EST) Congratulations on a great assignment. There are so many good things about this page. I think the biggest (and easiest) improvement to be made is to cut down on the amount of headings for the History and Current Research. The headings used such as "What did they do?" etc are helpful in showing the reader what exactly they are to understand from what is written, however they interrupt the flow and spread out the information so that it seems rather daunting. If you can summarise each section into a few sentences then I think that will not only reduce your contents section to a more useful size but also make the page more reader friendly. If you don't like that idea you could strike a happy medium by either having you "What did they do..." to bold instead of a heading or have (in bold or italics) a very short summary sentence under the name followed by a short few sentences. This would still give the reader an impression of what do get out of each section but would increase the flow inside and between notable researchers etc. Hope you find this helpful. :)

--[[User:Z3218146|Julianna Lam]] 01:31, 1 October 2009 (EST)
- the history section is TOO long ! the structure of the history section is good, i liked the whole idea of the sub headings ie ' what did he do?' but i think you guys included way too many people in there. the layout of the history section is not very neat and very inconsistent. you provided pictures of some people but didnt provide pictures of others. there are gaps everywhere and it just looks really messy.

- the stages and timeline parts are really good. the table looks really nice. and i especially like the pictures, very well labelled.

--[[User:Z3186093|Jenny Guy]] 18:46, 30 September 2009 (EST)

Improvements:
* The history is wayyyy too long. Seriously, there are too many sub sub sub headings. Cut it down and for each scientist make it a paragraph instead of so many dot points. I almost couldnt be bothered reading them all. Definitely not a good way to represent information. Looks as though you gave up on looking for pictures of the scientists. I would too if i had that many of them. Pick the main scientists that caused a breakthrough instead of listing all 1000 of them. Also, it is inconsistent if you did decide to keep the subsubsubsub headings as 'what he did', "what he found" and "what the importance" are generally all targeting the same question.
* I think you guys are confused as your information is conflicting. Humans have 23 pairs of chromosomes. In your introduction you state they humans and mice have the same number. However in the genetics it states that mice have 20pairs. What is true?
* There are a few gaps (large random spaces) in the genetics sections. Might want to format this a little.
* For the current research see the same massive point i mentioned first....
* Your referencing in the bibliography is inconsistent. Stick with one type of system, e.g. apa OR harvard. Some of the references aren't even referenced properly. You must reference websites.
* You haven't referenced ANY of you text. How do we know you havent just cut and paste? You need to either reference within the text (e.g. Andrews, E.A. (1895) states .....) or at the end of sentences/paragraphs with (Andrews 1895) or the number used in the bibliography.

--[[User:Z3255007|Sadaf Masood]] 15:43, 30 September 2009 (EST)Hey Group 4! Congrats on your great project guys! I have listed few points that might help:

1. Very well researched History section, lots of people doin lots of work..maybe you can make it a little short as its just a little too much info on them.

2. A bit more proper formatting, lots of gaps after every picture and table, maybe you can get rid of them

3. Timeline is great, just enough info to make sense and needed.

4. 'Why use of mouse is important?' this issue is well discussed. Great work!

5. Impressive hand drawn diagrams, any chances of making them a little larger on the main page? it would look really good!

6. Glossary is also needed...will make our life easier is understanding few words.

Rest is all well guys. The current research Section is awesome, very informative and lots of details. Its a great project guys...Best of Luck!!

--[[User:Z3218792|Gabriela Pinget]] 12:59, 30 September 2009 (EST) Hello! constructive criticism as follows:

- intro is a nice ease in but needs to be edited for grammar

- wow the history section is very well researched. I like that you've included so many contributors but are you sure you need to go into so much detail? It looks a little cluttered and detracts from the overall purpose of the assignment. Think about cutting down on it a little

- I really like the ''staging of embryonic development'' section! very engaging and well formatted! well done

-I also liked the timeline of development. I like that there was not too much information at each stage, but just enough to give a clear outline. Maybe a link to find out more would be useful

- genetics section is perfect

- again, the current research section is a little too spread out. The continuous "what did they do..." works well to begin with but after a while gets to be too much

Overall, a really nice looking page

--[[User:Z3295026|Joe Nassif]] 17:59, 29 September 2009 (EST)

Awesome looking wiki page, mouse group 4 an excellent assignment.

It is a really interesting reading and viewing your wiki page the content flow really well when reviewed.

1. The assignment is impressive it outlines the point with the use of sub headings which is always useful in the project as a referencing point.

2. (What did he do?) and (What did they find?) is a great way to state the history as it allows the reader to quickly get the brief information and understand it , also the illustrations throughout the assessment was great it referred to the text really well, which supported the info impressively. The hand drawn images in the (staging) and (timeline) sections were extremely great the detail was impressive.

3. Some ways to improve the assignment:
A) There are some unnecessary data throughout the project which are not relevant for example the ‘length of mouse embryo’ , removing this sections can truncate the assignment which would enhance the structure.

B) Current research information on the background of the research finders reveal great info on the development of the model usage, the findings and the relevance to human embryology have been summarized greatly.

C) The referencing need to be fixed in proper format. Visit : www.lc.unsw.edu.au/onlib/ref_apa.html for help with APA referencing

D) a glossary is needed to help the reader understand terms.

Overall a great project. The criteria was covered really well it, stated specfic topic in regards to the mouse and it embryonic developent which group 4 has summarised really well.

--[[User:Z3295026|Joe Nassif]] 17:59, 29 September 2009 (EST)

--[[User:Z3217015|Mitchell Mathieson]] 09:39, 25 September 2009 (EST)Page looks good. I liked how there was heaps of information on the genetics and the current research (however, this was a bit too spread out maybe). There seems to be a lot of gaps in the text, so the formatting could be maybe tightened up. The references maybe should be formatted better, and there is repeated information (tables and text for stages), but I really like how clicking the image goes to another page with more information...that is cool. The drawings are cute as well. Overall very good, I think formatting was the downfall from that, but the information is top notch.

--[[User:Z3126328|Jin Lee]] 16:42, 26 September 2009 (EST) hellow group4~ very impressive assignment guys!well done! I really enjoyed reading your assignment. it was easy to read and the information was relevant. However, I found the formatting of the images and texts were too sqeezy. may be resize the images and line up with the relevant information. Also, I think the reference needs to be looked after as well. Overall, the contents of the assignment is very useful and interesting.

--[[User:Z3187802|Vishnnu Shanmugam]] 20:02, 26 September 2009 (EST)Congratulations mouse group on an excellent assignment. It is a real joy to read. One of the best features of the assignment is how it gets straight to the point with the use of sub headings “What did he do?” & “What did they find?”. Even the images used throughout the text are interesting, especially the fully labeled hand drawn images in the “staging” and “timeline” sections. Some ways to improve the assignment:

-There are some unnecessary graphs in the assignment such as “the average length of mouse embryo”, “number of cells” and “number of somites”. These could perhaps be combined into a single graph. It will also reduce the congested appearance of the assignment as it seems too densely packed with no particular focus.

- In current research section, it is advisable to reduce the number of research and focus on just a few but provide more comprehensive information on the background of the research, the findings and the relevance to human embryology. It currently contains too many different types of research that have described very briefly.

- Edit the "content" section at the top of the page as it's length seems to be getting out of control. It is perhaps better to exclude the sub headings “What did he do?” & “What did they find?” in the contents.

- The referencing in the text need to be completed as there are some sections well referenced and others with no referencing. see www.lc.unsw.edu.au/onlib/ref_apa.html for help with APA referencing

- A Glossary would also complement the text.

Overall a classy project, only some changes necessary

--[[User:Z3126345|Gang Liu]] 16:49, 27 September 2009 (EST)This is one of the better wikipage i have seen so far. It demonstrates not only extended literature research skill, but also an in-depth understanding of the topic. The content of this page has been consistent throughout. In addition, paragraphs are straigtforward and concise, and make the point. Detailed texts with accessory graphics are appropriate in here. In paticular, history section. It describes the model use in terms of details of experiment, and results of experiment. Stages and timeline are very self-explanatory and visually enhanced.

This project can be improved by considering the following points.

*Lack of glossary list. Need to provide meaning of words such as "polyestrous", "oocyte", "Ectoderm", "endoderm", etc;

*Reformat stages section. I found this section a bit "busy". Might considering resize the pictures.

Last few words. I have learnt from this page that mouse has the same size genome as the human genome; Mouse genes can be easily manipulated and studied; Mouse a high degree of homogeny with humans. Well done!

--[[User:Z3217686|Thomas Dangerfield]] 14:12, 28 September 2009 (EST)Hey guys! Wow so much info first off! Not entirely sure we need to know about everyone involved in the history, maybe could have collaborated and joined people together or possibly even left certain people out. To me, the whole page is like how mark described, with everything all one great smudge of info with no real formatting or sequence or continuation. It was just kind of like an overload and reading it was a little difficult at some stages. Also corresponding the images in the timeline could have been included in the text.

Also I think your numbering of figures is a little off in the timeline section, with figures 1-4 on the right and then you have figures 4-7 describing stages 12-14. Just seems that there is two figure 4's for two different images.

Love the large amount of research and information, but could just work on your presentation and you'll do fine! Great work guys!

--[[User:Z3185685|Sumaiya Rahman]] 16:56, 28 September 2009 (EST) Hey guys! Overall a very nice assignment with a great deal of information! You can tell you guys did a lot of research. The contents are massive! Maybe you could cut this down and not use so many subheadings such as “what did they do?”, “what did they find?” and only have a subheading for each researcher. The introduction is well written. The history of model use has some really good information. My only criticism in this section is that there are a lot of gaps and blank spaces. You just need to delete all the spaces. The staging section showed a lot of research and effort. Well done!! The only thing is, is it a bit too much? There are a lot of tables and images that it was hard to keep track. Maybe this could be set out differently and made to look less busy. The timeline of development is fantastic and set out really well. It is very easy to understand and the drawings are great! Once again the current research is very spread out with lots of spaces. Also adding a glossary may help the readers in understanding the text. GREAT JOB!

--[[User:Z3215682|Carly Mooney]] 11:49, 29 September 2009 (EST)
I think all your material is there but the page layout needs work. Especially the history of the models use.
*The spacing and images are inconsistent. I liked the history of timeline section information and how it was presented, just the spacing of it all needs to be even.
*The stages of embryonic development was a little all over the place, and very daunting to look at.
*A glossary would help.
I think you guys did a really good job and just have to work on presentation.

--[[User:Z3220040|Joanne Raffel]] 16:14, 29 September 2009 (EST) Very impressive page, however it was very long!!! The introduction was very clear and concise. The history section was extremely long and poorly formatted, there were too many pictures with too little information, I would recommend cutting some of the images and just keeping the pictures of those who made a significant impact upon the mouse embryo, I also thought it was unneccessary to write after each subheading, what did he do and their result, I would prefer if it was just one paragraph. Your main heading were overshadowed by the subheadings and the rest of the text. There is a lot of information for the staging section, which is good however it can made it difficult to read, I would recommend having some of the information linked onto a separate page. The picture and format for the timeline section was exceptional however it lacked information, I also thought that it was irrelevent rewriting the timeline after the pictures, I would recommend including it with the picture rather than after it and the graph size made it seem insignificant. The genetics section was very extensive and I thought some of the information was better included with the current research. Similar to the history section, I thought the formatting of the current research section was very unorganised and too spaced out. Overall a very nice page.

----

--[[User:S8600021|Mark Hill]] 01:46, 8 September 2009 (EST) Well the content is there now, but what a mess, and I am not just talking about the formatting problem which can be easily fixed, you have no structure to your project, its not a matter of throwing everything at a wall and seeing what sticks. Work together for an integrated coverage. Timeline of development, is not the way to start your page with a huge table of data.

--[[User:S8600021|Mark Hill]] 08:43, 21 August 2009 (EST) OK guys, time to see some actual content uploaded on both your discussion and project pages.

* Timeline of Development - how long (Emily)
* Staging - are there species specific staging, what occurs when (Elide)
* History of Model Use - when was it first used, what embryology research (Begum)
* Genetics - chromosome number, sequencing (Angama)
* Current Embryology Research - research papers and findings (All)

Here is a link for timeline
[http://books.google.com.au/books?id=XLIarRWHikAC&pg=PT199&lpg=PT199&dq=mouse+embryo+development+timeline&source=bl&ots=fobLBRiacx&sig=cK4cuZah6Ksczs3o8v4NXQqoAyk&hl=en&ei=rGB6SvTHMMmIkAXB_piAAw&sa=X&oi=book_result&ct=result&resnum=3#v=onepage&q=&f=false
]

link for the mouse brain development timeline http://en.wikipedia.org/wiki/Mouse_brain_development_timeline

hey guys there is another interesting link about mouse development http://mouseatlas.caltech.edu/index_content.html

Hey Emily. The link below has a timeline that you can check out in your spare time. Begum.
[http://books.google.com.au/books?id=4juoa5xMs8oC&pg=PA31&lpg=PA31&dq=mouse+embryology&source=bl&ots=9tJAfRG4R6&sig=hjR5Zs-sL1sCW5FY8FnR5TMaUk0&hl=en&ei=LuuMSr_aCNjakAX714icDA&sa=X&oi=book_result&ct=result&resnum=9#v=onepage&q=mouse%20embryology&f=false]

Hi girls,
here is a link to a text book about mouse embryology it looks pretty good. hope it can help
[http://books.google.com.au/books?id=4juoa5xMs8oC&printsec=frontcover&dq=mouse+development&source=gbs_similarbooks_r&cad=2#v=onepage&q=mouse%20development&f=false]
let me know if the link doesnt work. Ive been working on the main page, so have a look and tell me what you think, Also what are we doing about references? If we have used information but put it in our own words do we need to put in text citations,or do we just reference the journal at the end? I just want to be very careful. Thanks!

Hey Elide, i think your work is looking really good. its very easy to read and understand. keep going!!!! emily

hey everyone,
I have uploaded some of my timeline work. I'm not sure if I've gone into to much detail or not and also on how is best to present the timeline. It is fairly basic and definately needs some work - especially on presentation, grammar, etc. let me know what you think.
Emily

good site for stages or timeline- atlas of pictures of stages- The Edinburgh Mouse Atlas Project [http://genex.hgu.mrc.ac.uk/]

Hello girls, it's Begum. I put some info under the history section. Wanted to let you all know that I've got a fair bit of info, and I will do my part as best as I can. Btw Emily, I think maybe dot from would be best for you, but if you can use those lines that I was talking to you about on Wednesday, that would be great...I know it's hard.

hey everyone, i have put some info under the genetics heading and some under research. I am still struggling to find the appropriate info related to the topic of genetics because there is alot of info abt the different types of stains used in labarotories but not the genetics. I emailed Dr.Hill and have asked him what to include in my section specifically,hopefully he will help. So far i have just started it needs alot of more work to be done,girls just read thru my section n leme know wt u think of it. have a nice weekend everyone. Angama.

Hi girls!
Begum, you history info is really good. If very interesting! I really like how you are doing it in order of dates of discovery and what they did, what they found etc! Cant wait to know more.
Angama, your doing well! it sounds like your finding the info hard to get. I'll keep an eye out for you! If your stuck on what you sound be doing then i might have a few ideas. I remember Mark Hill saying that you should compare the genome to the humans genome. so maybe if the genome is the same size as the humans, could you descibe similarities or differences? I know that there is a link to the mouse genome on the mouse web page he gave us ( next to the discussion link). Are you just ment to list the mouse genome sequence? could you go into what genes code what, eg which one codes for the sex linked gene, is it the X and Y gene etc? hopefully Mark gives you some ideas.
well as you might have noticed i've been adding to my stages. the only thing is im worried about there being too much info up there. basically ive tried to get all the info available included in my stages to make sure i cover everything, and then later i'll go over it all and edit and polish it up a bit. Ive done some drawings to the best of my ability, but i can scrap them if you all think they arnt professional enough. just thought i'd try to present the information differently. let me know if you think i'm including too much information. i think i'm having the same problem as you begum, there is lots of info! Elide

Thanks Elide. I'm trying. (Again, loved the artwork!)Btw, Emily, I had a think about your section and I think it might be too much 'clicking' back-and-forth if we link the displayed pic to the 'info' page. Don't stress, you've got the info (heaps which is excellent) but make sure you get some pictures soon so we can start drawing (I'm helping with the drawings as well ok). Mark said 'Nature' and 'Science' have useable images so lets make that our start.
BTW, I will be using the question mark symbol(???) so I don't forget to reference. Begum

Hey everyone, I have found an online text book. it has a chapter on genetics and history and a lot of other stuff. [http://books.google.com.au/books?id=Vt6nUmz1yEQC&pg=RA1-PA207&dq=mouse+development+anatomy&client=firefox-a#v=onepage&q=mouse%20development%20anatomy&f=false] Emily

Hey girls. If you've seen my section, the info is not on the main page, but linked to another page. I thought that it might make everything look more neat. I thought we could all do it like that. It's just an idea. Something different. Maybe we could have something on the main page (picture of a mouse). Your thoughts everybody? Begum

hey begum, ur work looks really good. i like the idea of linking the work to another page. - we don't have to worry about to much info being on the front page and it gives people to option of viewing the work if they want to. ive been working on drawings, i'll show them to you next week but am not sure how to upload them at the moment. Emily

Thanks! That sounds great that you like the idea. About the photos that you are drawing, if there by hand, you can scan them somehow. But overall,
1. click 'Upload File' on the left hand side of this page
2. New page comes up: click 'Browse' and choose your file that you want to upload.
3. Name it (under the Browse button)
NOTE: write down what you named the file as because like Elide says "...it's going to be lost in space!..."
4. Write down info/comments (like who is the author (YOU), and if the drawing is based on a picture)
5. UPLOAD!
6. Go to your section and just normally type this down to the area you want the picture to be seen:
[[image:THE NAME THAT YOU SAVED THE FILE UNDER.jpg|thumb|200px|right|WHAT YOU WANT THE FILE NAME TO VISUALLY COME UP AS]]

Your thoughts Angama and Elide? (about the linking of our sections to separate pages?) Begum.

Oh and another thing:
What do you girls think about my page, I've got a heading for each DATE and underneath each there are further subheadings (e.g. 'What did he do?'. Should I change them to just text, I mean, does it look messy with sub-sub-headings? Begum.

wow girls! great work.. okay so i asked mark about a new page and he said to avoid it because our info is meant to be on our one page. he said if there is extra information on what we wanted to say but is too much for the main page then have a link to our discussion page. (which is what im going to do) Begum your new page is fantastic!! you have done lots of work! but why dont you just put it on our main page? also girls i think we are getting too carried away with info. just keep it simple! i'm sorry i havent been around this week to work on it but i plan to get going asap. just fixing up some things, summarising, writing introductions etc.
did you all read his note about slabbing info onto our page?? how about some introductions, and sentences to ease ourselves into the content. planning on trying to work on that now anyway..

also lets get the information flowing. why dont we go intro, history of model use, stages, timeline, genetics, then current use.. what do you all think?

hey, i thing that that sounds like a good, logical way to do the page. i've finished the drawings, just need to upload them. About the timeline information, is there anything specific that i should include. the stuff that is on the page is a little vague and so i need some advice as to what are key points that i should include. i know that the drawing are very simplistic, let me know wjat you think about them. ive put one up below. i just need a way to link it to text. emily

Thanks Elide. You know, I think that's a great idea. Have it all on one page, seems less 'diverging...', seems more COMPLETE. I love the ORDER as well. I'll fix all that up!

Hey girls, please have a look at what i've done on the timeline. the images are all hand drawn based upon the text: 'the house mouse'. if anyone could give me any ideas on how best to present the pictures - which would be better - next to or below the text? keep in mind that it is incomplete and there is an illustration for each day of development (i.e. 19 in total). if you think that is too many let me know, some may be similar to Elide's ones. Also, do you think i should put some colour into the drawings? Emily

I love your work Emily. All you need to do is put the info on the growth of the mouse that is on the main page, onto the page with the graph of the growth of the mouse embryo...we talked about that before any way-AND I think your parts finished! Begum.
Angama, I added something to the end of your section that I thought was interesting. Have a look. And are you mentioning manipulation and 'shut-down' of the genes in your section?? Begum.
To everyone, apparently ''Mus Musculus'' is the scientific name of the common house mouse, not the mouse. I was thinking of editing that.

HEY EVERYONE! well i've added in some pictures just to make it look more visual, change them if you have better ones.. and i'm going to be working on the current research section tommorow. oh i also added some graphs like we thought of for emilys section.. so i think my section is finished finally! what do you think? can i just say, I think the whole thing looks great! you girls have been a pleasure to work with! :) Thanks so much!!

hi girls, i am sorry..i have been very busy during the mid-sem break and i know we all had our exams and assignments due. but i was having some issues in my family and also the exams and assignments so didnt really had the chance to read wat u girls have got on the main page. i just finished reading thru it and it looks amazing..WELL DONE GIRLS!! you all have done a marvellous job...Eldie and Begum thanks for suggesting some main points to add for the genetics.i am currently working on it.. hopefully tonight i will have all the information on the page..Begum i love how you have presented alot of info into a very easy and understandable way..it makes so much sense..n it looks very nice with the pictures. Eldie and Emily great amount of work and the pictures and the graphs are superb. i just had a look to other groups pages. n i think so far our page looks very interesting with concise info n amazing pictures. n Begum yes i read what you have added thanks for tht..i will cu girls around..gudluck everyone. cheers. Angama.

Girls can you please help me out.. i am so annoyed..
like rite now i was typing some info and when i clicked to save.
it says "conflict" so i think some one else is also editing
the page at the same time that i am. and i lost all my work..arghh..
so which means i have to type it all again.
is there any other way that it tells me that someone else
is also using it so i dont click on save or even preview
because when i do tht i lost all the work tht i had.
If anyone knows please let me know. thanks. Angama.

Current research : I have put some information in the current research part. not sure where they should be put. Begum, as discussed you can edit it or place it in its appropriate place.

Don't stress Angama at all, now you know, it will be over soon. Uploading it easy:

1. click 'Upload File' on the left hand side of this page

2. New page comes up: click 'Browse' and choose your file that you want to upload.

3. Name it (under the Browse button) NOTE: write down what you named the file as because like Elide says "...it's going to be lost in space!..."

4. Write down info/comments (like who is the author (YOU), and if the drawing is based on a picture)

5. UPLOAD! 6. Go to your section and just normally type this down to the area you want the picture to be seen:

It's easier than it is typed! Of you still have problems I will be at the embryo lab, of there is exams there the ANAT LAB opposite to it, if not Level 3 library computers.

[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19538749| maternal diabetes alters transcriptional programs in the developing embryo], [http://www.ncbi.nlm.nih.gov/pubmed/19414407?ordinalpos=35&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum|Abnormal mammary gland development in MMTV-CBLC transgenic mouse], [http://www.ncbi.nlm.nih.gov/pubmed/19394325?ordinalpos=40&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum|Sonic hedgehog signalling inhibits palatogenesis and arrests tooth development in a mouse model of the nevoid basal cell carcinoma syndrome.], [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=55&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum| Fibroblast growth factor 18 gives growth and directional cues to airway cartilage.]

Hi girls, i think i have completed my section. could you all please just read thru it and leme know wat you think of it. i did it to the best of my ability. Hopefully you will all like it if you girls think therez anything more to add or to delete leme know..thanks. gudluck girls. Angama.

Angama your work is fantastic! Thanks so much! im sorry i wasnt around to help you with the problems. hope it went okay. your info is perfect! im very happy with our page! lets hope everyone else is :)

I love it Angama, good work! And the pictures you uploaded are very interesting. Cool. Awesome. Your done!! Begum.

Thanks Begum :) Girls gudluck and cu all tomorrow. Angama.

== Discussion after peer assessment and constructive criticism ==

Hi girls,
Ive started making some changes to the page based on the comments recieved.
Note i've also started a glossary of terms. Also many of our comments regarded our references,so It would be great if we could all reference the same, lets say APA because this is the most common way for referencing. I have gone through our references and tried to format them in APA. many are incomplete references so i have bolded the references that are missing detail. please if you all could complete your references that you added to the list. Also shall we number the references so we can include the numbers in the text as in text references? like foot note? what do you all think... there have been many comments on our current research page.. so how would you all like to fix it? I personally think its way too much. It seems to have accumulated heaps of info from when I last saw it. Is there anyway of summarising the current research info to focus more on how they are used rather than the institute and scientists involved. I think the most important info in this section is what mice are being used to discover currently and proof of the year of study. Cant wait to hear what you all think! Elide

one more thing.. ive tried to edit the contents, as one of our peers suggested, however i cant seem to edit it. do any of you know how to do this?
Elide

hey emily, i see you have reduced the heading in the contents!! thats great! i was just thinking that maybe we dont need so many headings in those 2 sections at all. what do you think about just making all the scientists and the names of people/ labs just in bold.?

Hi girls, have a look at the changes i have made to my section. let me know what you think. Emily

looks good!!
also girls could you please add words from your sections to the glossary, as that whole list is only from the staging section. thanks. elide

Hello girls. I will be re-formatting the history section in order to get rid of the 'gaps' that my peers have mentioned. Also, Elide mentioned yesterday that placing all the 'History' pictures towards the right-side of the page would look more neat, as well as add to the flow of the page. I think this is a great idea. Begum. Oh, and '''what do you guys think about taking out some information (findings)?''' Some students have mentioned that there is too much information/researchers.
And Elide, I'm might change the names of the researchers. like you said before, to bolded text. It would look much more neat. I might, also, '''apply this to the Genetics section. What do you all think?'''

'''Begum's Problem'''
Hey. I placed all pictures to the right-hand side (history section), but the pictures don't correspond well with the text. Any suggestions?? Should I than put the towards the left? Love the change to the timeline section Emily.

HEY BEGUM!!
so your problem.. I dont think the pictures need to match up because if they have a title of the person then the reader can find their picture. plus the comments are on the spaces and gaps between text, not the pictures.. so maybe just put them all underneath each other and even if they dont match up then at least the writing looks more organised. try making the images 200px and not so large and it could work better?. also the bit about taking out the headings in the genetics would be great!! bold would still look fine! goodluck! xox

--[[User:Z3254857|Begum Sonmez]] 14:54, 10 October 2009 (EST) '''TO ELIDE''': I was going to change the headings 'Reproduction' and 'Theiler Stages' under STAGES to bolded text. What do you think? Plus, like you said before, I'm on that ref. list, I will summarise the current research, and change those headings. If the HISTORY pictures match up to the the text, it would be more convenient for the viewer, don't you all think so??? However, the text would appear better the other way with the images al together on the right. Yes, I'll do that.

Hey '''Begum'''!
yes what a great idea about changing the headings in the staging section! the whole page needs to have the same structure throughout! I shall change them right now! :) i'm a little confused about the bit you said about what you said about the ref list. do you mean that you will fix yours? ive been through some of them and looked up the missing details. some are lacking their full reference though. but that would be so great if you could fix up your references. i think the ones in bold are the ones still needing work, but correct the others if you think they arent finished.
well i think the history section looks great! even though the pictures dont match up, they are still there and they look neat and have the same format as the rest of the page. and even better there are no spaces! so it looks great!! i wouldnt worry too much, you've done a such great job providing detail, the pictures are just a bonus!
the reference list looks great! thanks for your help! xox Elide

--[[User:Z3254857|Begum Sonmez]] 20:55, 11 October 2009 (EST)Hello girls! One more thing left: Current Research section. One student said to reduce the number of 'research', but include more information on each. I don't think adding more info under the research is necessary. But '''just keeping the 'breakthroughs'''' would be good, the more important ones. What do you all think? Also, '''what should the headings be''', any suggestion? Should I keep the Organisations as the headings, or the names of the researchers involoved, and/or the dates?

--[[User:Z3224449|Elide Newton]] 11:41, 12 October 2009 (EST) hey. about the current research section. well now that it doesnt have as many spaces and gaps it doesnt look as long, so maybe thats why the student saids to reduce the number of examples. so i'm with you begum, keep the important ones. for example if there are 2 examples of its use in cancer then have only one cancer example. yes headings . i think maybe keep the organisation and date. see what the other girls think.. i'll have a think about it too, and see what we can improve on that section.. overall are we all happy with how its looking? i think its looking great! even the reference list doesnt look messy! :)

== List of things still to do ==
* Check the reference list to see bold references, if these are yours please complete the reference
* formating (remove spaces, make it look neater, make sure the same format is used throughout the whole page)
* add glossary terms
* fix up current research! its really messy!!
* proof read the whole thing
* check if your images have info underneath, reference and copyright liscence.
* remove headings from genetics section

What else do you think needs fixing? these are just some things i know we need to do. Elide xo

== Changes made ==
--[[User:Z3224449|Elide Newton]] 12:17, 2 October 2009 (EST)
*Removed table of stages from discussion page
*Corrected introduction " the mouse has a similar genome to the human"
*In stages section changed size of images to 200px and moved to the right
*Removed spaces and gaps from stages
*Formated stages section to look neater
*Deleted the links to tables on discussion page
*Added in table of theiler stages 12-14 which was on the discussion page
*Started a glossary of terms
--[[User:Z3224449|Elide Newton]] 16:17, 5 October 2009 (EST)
*Added in text citations to the staging section
*Added in more definitions for glossary of terms and referenced glossary
*Went through each reference of reference list and changed the format it into APA, bold for incomplete references.. to note that it needs to be fixed.

--[[User:Z3252340|Emily Wong]] 11:28, 6 October 2009 (EST)
* Edited the contents so that it wasn't as long i.e. took out all the repeated "what did he do?" etcs.
* Edited current research so that contents are not as long. Again taking out the "what did the do" etcs.
--[[User:Z3252340|Emily Wong]] 15:38, 8 October 2009 (EST)
* Edited the timeline of development section by:
** Taking out the written text and incorporated it into the captions below each drawing.
** Rearranging the work so that it was in a better position
** Linked the graph 'Average length of the mouse embryo' into the section by writing a small blurb on it.

--[[User:Z3224449|Elide Newton]] 10:44, 9 October 2009 (EST)
* Removed spaces in sections current research and genetics
* Moved images to the right and changed size to 200px in current research section
* re-uploaded theiler stage 8 image with typo fixed ( reichards to Reicherts)
* added information below images in the staging section.
* added links to source below images in staging section
* deleted 'Photo of mouse vascular development at Theiler stage 20' because I am unable to find copyright liscence
* went through each ref and chagned to APA, had to look up dates and authors for incomplete references added by other students. still some are not complete (in bold) so if you added these references could you please fix.

--[[User:Z3254857|Begum Sonmez]] 12:28, 9 October 2009 (EST)
*Changed the heading 'Chromosome number and banding patterns' under Genetics, from being a main heading to a sub-heading. This was a small mistake that had to be fixed.
*Changed the sub-headings of the history section, that list the years, to bolded text. The reason for this change is that it condensed the amount of headings in the 'Contents', allowing the viewer to have an outline of the page instead of a massive list of each heading. As a result, the page looks more neat, and each section is consistent with eachother.
*Placed all pictures in the History section to the right-side of the page. This is more consistent with the rest of the page, and adds to the flow of the page.
*Placed 2 spaces between each finding, and 1 space between each part of the finding (For example, 'What did they find', 'The Importance'). Again, this is another feature which adds to the consistancy of the page. Many of our peers pointed out that our page was messy. This change helps to solve the problem.

--[[User:Z3224449|Elide Newton]] 20:38, 9 October 2009 (EST)
*Removed headings from current research section and made them bold.
*Finished the glossary of terms from the staging section
*worked on current research. (removed spaces, formated, removed lists of names and added 'et al')

--[[User:Z3254857|Begum Sonmez]] 14:45, 10 October 2009 (EST)
*Changed the sub-headings under the Genetics section to bolded text. There were no complaints about this from our peers. However, since this was applied to the History section, applying it to the Genetics section would be consistent and more neat.
*Placed all HISTORY pictures beneath one another in order to be consistent with the arrangement of other pictures throughout the page.
*Deleted some of the headings (what did they, how did they...) under the history section, as the contents of some of the headings were related. One student mentioned this. As a result, there is less headings, and a greater degree of clarity.
*Edited the Reference list by dividing it into 2 headings ('Books and Articles' and 'Webpage'), and converted some more references into APA style. Just one more conversion left.
*Added the definitions of 'Allophenic', 'Chimera', 'Corpus luteum', 'Somatic tissue' and 'Stem Cell' to the Glossary List.

--[[User:Z3224449|Elide Newton]] 19:44, 10 October 2009 (EST)
*Removed headings from staging section and made bold instead to be the same as the whole page
*Removed two gaps from the genetics section

--[[User:Z3254857|Begum Sonmez]] 14:24, 12 October 2009 (EST)
*Changed some of the Sub-headings under the Current Research section to make it more consistent throughout this section.
*Converted the information under each finding under the Current Research section into numerous small paragraphs because one student outlined that the use of the sub-sub-headings were good at first, but it than became overwhelming. This change enhanced the layout without using the sub-sub-headings and without ending up with a slab of text.

--[[User:Z3254857|Begum Sonmez]] 11:18, 13 October 2009 (EST)
*Changes the heading 'THE MOUSE' from all upper-case to lower-case. This is consistent with the other main headings.

2009 Group Project 4

2009-10-13T00:17:19Z

Z3254857: /* THE MOUSE (Mus musculus) */

== The Mouse (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Are small organisms which can be easily maintained
*Are not expensive
----
===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:Wesley_Whitten.jpg|thumb|200px|right|Wesley K. Whitten]]
[[image:Dame_Anne_Laura_Dorinthea_McLaren.jpg|thumb|200px|right|Dame Anne Laura Dorinthea McLaren]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Beatrice_Mintz.jpg|thumb|200px|right|Beatrice Mintz]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]
[[image:Teruhiko_Wakayama.jpg|thumb|200px|right|Teruhiko Wakayama]]
[[image:Leroy_Stevens.jpg|thumb|200px|right|Leroy Stevens]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Gingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development so far a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development clink the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm.
{{Insert timeline}}
----
===Genetics===
[[image:Genetics_of_laboratory_rodents.jpg|thumb|200px|right|Genetics of labarotory rodents]]

'''Genome'''

Sequencing of the mouse genome was completed in late 2002. Tha haploid genome is about 3 billion long (3000 Mb distributed over 20 chromosomes) and therefore equal to the size of the human genome. The current estimated gene count is 23,786 and humans are estimated to have 23,686 genes.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino (Haldane et al., 1915)
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).

'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome (Laird, 1971). Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.
[[image:Mice_expressing_GFP.jpg|thumb|200px|right|Mice expressing GFP]]
Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function (Hood, 1992). However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

[[image:Figure3-3.jpg‎|thumb|200px|right|Examples of some commonly used mouse strains]]
[[image:Transgenicmouse.jpg|thumb|200px|right|Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition]]
Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]
[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve din mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===
[[image:nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
[[image:NIDCR.jpg|thumb|200px|right|Members of NIDCR]]

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the in organising the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:
1.Supports the multiplication of the H9 cells better than the 3T3 line.
2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: ''An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells''. Link to Abstract [http://www.library.unsw.edu.au/cgi-bin/Data/db.cgi?db=fulltexttest&uid=default&view_records=1&url=http://gateway.proquest.com/openurl?atitle=Harvard+University,+School+of+Medicine;+Human+embryonic+stem+cells+propagated+on+immortalized+drug-resistant+cell+line&date=2006&rft_val_fmt=ori:fmt:kev:mtx:journal&spage=236&issn=1551-529X&ctx_ver=Z39.88-2003&genre=article&res_id=xri:pqd&req_dat=xri:pqil:pq_clntid=&Address=http://gateway.proqu] or [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155) - an Alox5-deficient mouse on a B6 background, and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on mormal HSCs.

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy will be clinically trialed in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia, et al. used the knock out mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knouck out mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cell differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ here].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in critical developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. used the mouse as a model organism to study the epithelial - mesenchymal crosstalk that occurs in Wolffian duct and testis cord development. They found that the epithelial-mesenchymal interactions in the development of these two male structures are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins when mutated become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin rather than the bacterial cell numbers is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab on the mice containing EGFR mutated lung tumors.

It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''' which has been studied to assist in generating antibody and CD4 T helper cell responses.

This process, explained above, was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

{{Template:Projects09}}
[[Category:Mouse]]

Talk:2009 Group Project 4

2009-10-12T03:24:34Z

Z3254857: /* Changes made */

== Project Updates ==
--[[User:Z3283499|Antonio Lee]] 10:57, 2 October 2009 (EST) Hi everyone, I will be working with you during the Lab10 Tutorial and here is the news link and PDF of the manuscript for your group exercise. I encourage you to read the paper before the tutorial. Also, please indicate next to the questions below (using either your initials or student number) which one of the four questions you wish to address.
:'''Group 4 :''' [http://www.scientificamerican.com/article.cfm?id=stem-cells-from-fat-cells '''Induced Pluripotent Stem Cells Created from Fat Cells'''] in Scientific American Published online 8 September 2009 [[Media:ANAT2341_Lab10_2009_Group 4 Reading.pdf|Manuscript (PDF): Feeder-free derivation of induced pluripotent stem cells from adult human adipose stem cells]]

:Question 1. What is the background to the existing problem / disease condition?--[[User:Z3252340|Emily Wong]] 13:41, 8 October 2009 (EST)
:Question 2. What approach / method did the research team take to tackle / improve the problem? --[[User:Z3252231|Angama Yaquobi]] 19:27, 7 October 2009 (EST)(Angama Yaquobi)
:Question 3. What was the breakthrough / major advancement OR failure / drawback? and why might this be of significance?--[[User:Z3224449|Elide Newton]] 13:43, 8 October 2009 (EST)
:Question 4. What are the next steps in moving forward? What are the next or new hurdles to overcome?--[[User:Z3254857|Begum Sonmez]] 12:42, 8 October 2009 (EST)

==Constructive Criticism of Coordinator==
--[[User:S8600021|Mark Hill]] 08:07, 8 October 2009 (EST) The following comments are general in nature in no specific order, as it would be inappropriate to suggest specific changes and then assess the final project. Comments will be added during this week and you still have one week before final submission.

* The project has improved in content and layout from the original submission date.
* A general comment about images. When you click an image and it opens, the information below the image should have an explanation of what the image shows, a reference (if from a paper) and a link to the original source (if available) as well as copyright information.
* There are still issues related to page design with large white spaces visible.
* [[:File:Mice_expressing_GFP.jpg]] What is the original source of this image? Do you have permission to reuse?
* [[:File:Genetics of laboratory rodents.jpg]] What is this transgenic mouse expression pattern showing?
* The Theiler images of embryo stages are useful to have, are they really all redrawn? I will be comparing these to the original online versions and they cannot be direct copies without permission.
* [[:File:Mouse_theiler_stage8.JPG]] Reichard's menbrane?
* Glossary still incomplete.
* Reference could be tidied up.

==Constructive Criticism of Peers==

--[[User:Z3218657|Sally Clarke]] 09:59, 1 October 2009 (EST)Well Done!

I'm just jumping straight into it..

- I Think the timeline stage is fantastic - the images and information are displayed really well

- the staging information is a little cramped and thrown in together - it doesn't flow very well and the images are all over the shop

- The history section has A LOT of information an images of the scientists, what they did and how they did it - great... i know this would have taken a lot of work but its a bit long. I think maybe making it into a timeline on different pages might help this.

- The headings and sub headings are really good and informative but there is a few formatting errors which is easy to fix

- The genetics sections is really good, nice and concise yet informative

Great assignment guys!

--[[User:Z3258567|Sando Rashed]] 09:12, 1 October 2009 (EST)hey wow lots of information in this page :D, well done with the effort use all put in it looks and sounds goood, few things im not sure if it was my computer but staging of embryonic development there was just a bunch of photos and they were crammed up and overlapping each other making it very hard to read use might want to cut down on the photos in that area or scale them down to make it easier to read. you have a lot of information in your history section its good that you have what they do and their contribution to make it look a bit better you might want to split it up into a 3 way table (name/what they do/how it helped) minimise the reading as i recall dr mark saying to much reading is not something he wants he wants something more appealing to him where he can lay in bed and mark it without falling asleep so a table would be good here. other than that its a great page :D well done hope use all do well!!

--[[User:Z3223194|Bronwyn Lewis-Jones]] 08:53, 1 October 2009 (EST) Congratulations on a great assignment. There are so many good things about this page. I think the biggest (and easiest) improvement to be made is to cut down on the amount of headings for the History and Current Research. The headings used such as "What did they do?" etc are helpful in showing the reader what exactly they are to understand from what is written, however they interrupt the flow and spread out the information so that it seems rather daunting. If you can summarise each section into a few sentences then I think that will not only reduce your contents section to a more useful size but also make the page more reader friendly. If you don't like that idea you could strike a happy medium by either having you "What did they do..." to bold instead of a heading or have (in bold or italics) a very short summary sentence under the name followed by a short few sentences. This would still give the reader an impression of what do get out of each section but would increase the flow inside and between notable researchers etc. Hope you find this helpful. :)

--[[User:Z3218146|Julianna Lam]] 01:31, 1 October 2009 (EST)
- the history section is TOO long ! the structure of the history section is good, i liked the whole idea of the sub headings ie ' what did he do?' but i think you guys included way too many people in there. the layout of the history section is not very neat and very inconsistent. you provided pictures of some people but didnt provide pictures of others. there are gaps everywhere and it just looks really messy.

- the stages and timeline parts are really good. the table looks really nice. and i especially like the pictures, very well labelled.

--[[User:Z3186093|Jenny Guy]] 18:46, 30 September 2009 (EST)

Improvements:
* The history is wayyyy too long. Seriously, there are too many sub sub sub headings. Cut it down and for each scientist make it a paragraph instead of so many dot points. I almost couldnt be bothered reading them all. Definitely not a good way to represent information. Looks as though you gave up on looking for pictures of the scientists. I would too if i had that many of them. Pick the main scientists that caused a breakthrough instead of listing all 1000 of them. Also, it is inconsistent if you did decide to keep the subsubsubsub headings as 'what he did', "what he found" and "what the importance" are generally all targeting the same question.
* I think you guys are confused as your information is conflicting. Humans have 23 pairs of chromosomes. In your introduction you state they humans and mice have the same number. However in the genetics it states that mice have 20pairs. What is true?
* There are a few gaps (large random spaces) in the genetics sections. Might want to format this a little.
* For the current research see the same massive point i mentioned first....
* Your referencing in the bibliography is inconsistent. Stick with one type of system, e.g. apa OR harvard. Some of the references aren't even referenced properly. You must reference websites.
* You haven't referenced ANY of you text. How do we know you havent just cut and paste? You need to either reference within the text (e.g. Andrews, E.A. (1895) states .....) or at the end of sentences/paragraphs with (Andrews 1895) or the number used in the bibliography.

--[[User:Z3255007|Sadaf Masood]] 15:43, 30 September 2009 (EST)Hey Group 4! Congrats on your great project guys! I have listed few points that might help:

1. Very well researched History section, lots of people doin lots of work..maybe you can make it a little short as its just a little too much info on them.

2. A bit more proper formatting, lots of gaps after every picture and table, maybe you can get rid of them

3. Timeline is great, just enough info to make sense and needed.

4. 'Why use of mouse is important?' this issue is well discussed. Great work!

5. Impressive hand drawn diagrams, any chances of making them a little larger on the main page? it would look really good!

6. Glossary is also needed...will make our life easier is understanding few words.

Rest is all well guys. The current research Section is awesome, very informative and lots of details. Its a great project guys...Best of Luck!!

--[[User:Z3218792|Gabriela Pinget]] 12:59, 30 September 2009 (EST) Hello! constructive criticism as follows:

- intro is a nice ease in but needs to be edited for grammar

- wow the history section is very well researched. I like that you've included so many contributors but are you sure you need to go into so much detail? It looks a little cluttered and detracts from the overall purpose of the assignment. Think about cutting down on it a little

- I really like the ''staging of embryonic development'' section! very engaging and well formatted! well done

-I also liked the timeline of development. I like that there was not too much information at each stage, but just enough to give a clear outline. Maybe a link to find out more would be useful

- genetics section is perfect

- again, the current research section is a little too spread out. The continuous "what did they do..." works well to begin with but after a while gets to be too much

Overall, a really nice looking page

--[[User:Z3295026|Joe Nassif]] 17:59, 29 September 2009 (EST)

Awesome looking wiki page, mouse group 4 an excellent assignment.

It is a really interesting reading and viewing your wiki page the content flow really well when reviewed.

1. The assignment is impressive it outlines the point with the use of sub headings which is always useful in the project as a referencing point.

2. (What did he do?) and (What did they find?) is a great way to state the history as it allows the reader to quickly get the brief information and understand it , also the illustrations throughout the assessment was great it referred to the text really well, which supported the info impressively. The hand drawn images in the (staging) and (timeline) sections were extremely great the detail was impressive.

3. Some ways to improve the assignment:
A) There are some unnecessary data throughout the project which are not relevant for example the ‘length of mouse embryo’ , removing this sections can truncate the assignment which would enhance the structure.

B) Current research information on the background of the research finders reveal great info on the development of the model usage, the findings and the relevance to human embryology have been summarized greatly.

C) The referencing need to be fixed in proper format. Visit : www.lc.unsw.edu.au/onlib/ref_apa.html for help with APA referencing

D) a glossary is needed to help the reader understand terms.

Overall a great project. The criteria was covered really well it, stated specfic topic in regards to the mouse and it embryonic developent which group 4 has summarised really well.

--[[User:Z3295026|Joe Nassif]] 17:59, 29 September 2009 (EST)

--[[User:Z3217015|Mitchell Mathieson]] 09:39, 25 September 2009 (EST)Page looks good. I liked how there was heaps of information on the genetics and the current research (however, this was a bit too spread out maybe). There seems to be a lot of gaps in the text, so the formatting could be maybe tightened up. The references maybe should be formatted better, and there is repeated information (tables and text for stages), but I really like how clicking the image goes to another page with more information...that is cool. The drawings are cute as well. Overall very good, I think formatting was the downfall from that, but the information is top notch.

--[[User:Z3126328|Jin Lee]] 16:42, 26 September 2009 (EST) hellow group4~ very impressive assignment guys!well done! I really enjoyed reading your assignment. it was easy to read and the information was relevant. However, I found the formatting of the images and texts were too sqeezy. may be resize the images and line up with the relevant information. Also, I think the reference needs to be looked after as well. Overall, the contents of the assignment is very useful and interesting.

--[[User:Z3187802|Vishnnu Shanmugam]] 20:02, 26 September 2009 (EST)Congratulations mouse group on an excellent assignment. It is a real joy to read. One of the best features of the assignment is how it gets straight to the point with the use of sub headings “What did he do?” & “What did they find?”. Even the images used throughout the text are interesting, especially the fully labeled hand drawn images in the “staging” and “timeline” sections. Some ways to improve the assignment:

-There are some unnecessary graphs in the assignment such as “the average length of mouse embryo”, “number of cells” and “number of somites”. These could perhaps be combined into a single graph. It will also reduce the congested appearance of the assignment as it seems too densely packed with no particular focus.

- In current research section, it is advisable to reduce the number of research and focus on just a few but provide more comprehensive information on the background of the research, the findings and the relevance to human embryology. It currently contains too many different types of research that have described very briefly.

- Edit the "content" section at the top of the page as it's length seems to be getting out of control. It is perhaps better to exclude the sub headings “What did he do?” & “What did they find?” in the contents.

- The referencing in the text need to be completed as there are some sections well referenced and others with no referencing. see www.lc.unsw.edu.au/onlib/ref_apa.html for help with APA referencing

- A Glossary would also complement the text.

Overall a classy project, only some changes necessary

--[[User:Z3126345|Gang Liu]] 16:49, 27 September 2009 (EST)This is one of the better wikipage i have seen so far. It demonstrates not only extended literature research skill, but also an in-depth understanding of the topic. The content of this page has been consistent throughout. In addition, paragraphs are straigtforward and concise, and make the point. Detailed texts with accessory graphics are appropriate in here. In paticular, history section. It describes the model use in terms of details of experiment, and results of experiment. Stages and timeline are very self-explanatory and visually enhanced.

This project can be improved by considering the following points.

*Lack of glossary list. Need to provide meaning of words such as "polyestrous", "oocyte", "Ectoderm", "endoderm", etc;

*Reformat stages section. I found this section a bit "busy". Might considering resize the pictures.

Last few words. I have learnt from this page that mouse has the same size genome as the human genome; Mouse genes can be easily manipulated and studied; Mouse a high degree of homogeny with humans. Well done!

--[[User:Z3217686|Thomas Dangerfield]] 14:12, 28 September 2009 (EST)Hey guys! Wow so much info first off! Not entirely sure we need to know about everyone involved in the history, maybe could have collaborated and joined people together or possibly even left certain people out. To me, the whole page is like how mark described, with everything all one great smudge of info with no real formatting or sequence or continuation. It was just kind of like an overload and reading it was a little difficult at some stages. Also corresponding the images in the timeline could have been included in the text.

Also I think your numbering of figures is a little off in the timeline section, with figures 1-4 on the right and then you have figures 4-7 describing stages 12-14. Just seems that there is two figure 4's for two different images.

Love the large amount of research and information, but could just work on your presentation and you'll do fine! Great work guys!

--[[User:Z3185685|Sumaiya Rahman]] 16:56, 28 September 2009 (EST) Hey guys! Overall a very nice assignment with a great deal of information! You can tell you guys did a lot of research. The contents are massive! Maybe you could cut this down and not use so many subheadings such as “what did they do?”, “what did they find?” and only have a subheading for each researcher. The introduction is well written. The history of model use has some really good information. My only criticism in this section is that there are a lot of gaps and blank spaces. You just need to delete all the spaces. The staging section showed a lot of research and effort. Well done!! The only thing is, is it a bit too much? There are a lot of tables and images that it was hard to keep track. Maybe this could be set out differently and made to look less busy. The timeline of development is fantastic and set out really well. It is very easy to understand and the drawings are great! Once again the current research is very spread out with lots of spaces. Also adding a glossary may help the readers in understanding the text. GREAT JOB!

--[[User:Z3215682|Carly Mooney]] 11:49, 29 September 2009 (EST)
I think all your material is there but the page layout needs work. Especially the history of the models use.
*The spacing and images are inconsistent. I liked the history of timeline section information and how it was presented, just the spacing of it all needs to be even.
*The stages of embryonic development was a little all over the place, and very daunting to look at.
*A glossary would help.
I think you guys did a really good job and just have to work on presentation.

--[[User:Z3220040|Joanne Raffel]] 16:14, 29 September 2009 (EST) Very impressive page, however it was very long!!! The introduction was very clear and concise. The history section was extremely long and poorly formatted, there were too many pictures with too little information, I would recommend cutting some of the images and just keeping the pictures of those who made a significant impact upon the mouse embryo, I also thought it was unneccessary to write after each subheading, what did he do and their result, I would prefer if it was just one paragraph. Your main heading were overshadowed by the subheadings and the rest of the text. There is a lot of information for the staging section, which is good however it can made it difficult to read, I would recommend having some of the information linked onto a separate page. The picture and format for the timeline section was exceptional however it lacked information, I also thought that it was irrelevent rewriting the timeline after the pictures, I would recommend including it with the picture rather than after it and the graph size made it seem insignificant. The genetics section was very extensive and I thought some of the information was better included with the current research. Similar to the history section, I thought the formatting of the current research section was very unorganised and too spaced out. Overall a very nice page.

----

--[[User:S8600021|Mark Hill]] 01:46, 8 September 2009 (EST) Well the content is there now, but what a mess, and I am not just talking about the formatting problem which can be easily fixed, you have no structure to your project, its not a matter of throwing everything at a wall and seeing what sticks. Work together for an integrated coverage. Timeline of development, is not the way to start your page with a huge table of data.

--[[User:S8600021|Mark Hill]] 08:43, 21 August 2009 (EST) OK guys, time to see some actual content uploaded on both your discussion and project pages.

* Timeline of Development - how long (Emily)
* Staging - are there species specific staging, what occurs when (Elide)
* History of Model Use - when was it first used, what embryology research (Begum)
* Genetics - chromosome number, sequencing (Angama)
* Current Embryology Research - research papers and findings (All)

Here is a link for timeline
[http://books.google.com.au/books?id=XLIarRWHikAC&pg=PT199&lpg=PT199&dq=mouse+embryo+development+timeline&source=bl&ots=fobLBRiacx&sig=cK4cuZah6Ksczs3o8v4NXQqoAyk&hl=en&ei=rGB6SvTHMMmIkAXB_piAAw&sa=X&oi=book_result&ct=result&resnum=3#v=onepage&q=&f=false
]

link for the mouse brain development timeline http://en.wikipedia.org/wiki/Mouse_brain_development_timeline

hey guys there is another interesting link about mouse development http://mouseatlas.caltech.edu/index_content.html

Hey Emily. The link below has a timeline that you can check out in your spare time. Begum.
[http://books.google.com.au/books?id=4juoa5xMs8oC&pg=PA31&lpg=PA31&dq=mouse+embryology&source=bl&ots=9tJAfRG4R6&sig=hjR5Zs-sL1sCW5FY8FnR5TMaUk0&hl=en&ei=LuuMSr_aCNjakAX714icDA&sa=X&oi=book_result&ct=result&resnum=9#v=onepage&q=mouse%20embryology&f=false]

Hi girls,
here is a link to a text book about mouse embryology it looks pretty good. hope it can help
[http://books.google.com.au/books?id=4juoa5xMs8oC&printsec=frontcover&dq=mouse+development&source=gbs_similarbooks_r&cad=2#v=onepage&q=mouse%20development&f=false]
let me know if the link doesnt work. Ive been working on the main page, so have a look and tell me what you think, Also what are we doing about references? If we have used information but put it in our own words do we need to put in text citations,or do we just reference the journal at the end? I just want to be very careful. Thanks!

Hey Elide, i think your work is looking really good. its very easy to read and understand. keep going!!!! emily

hey everyone,
I have uploaded some of my timeline work. I'm not sure if I've gone into to much detail or not and also on how is best to present the timeline. It is fairly basic and definately needs some work - especially on presentation, grammar, etc. let me know what you think.
Emily

good site for stages or timeline- atlas of pictures of stages- The Edinburgh Mouse Atlas Project [http://genex.hgu.mrc.ac.uk/]

Hello girls, it's Begum. I put some info under the history section. Wanted to let you all know that I've got a fair bit of info, and I will do my part as best as I can. Btw Emily, I think maybe dot from would be best for you, but if you can use those lines that I was talking to you about on Wednesday, that would be great...I know it's hard.

hey everyone, i have put some info under the genetics heading and some under research. I am still struggling to find the appropriate info related to the topic of genetics because there is alot of info abt the different types of stains used in labarotories but not the genetics. I emailed Dr.Hill and have asked him what to include in my section specifically,hopefully he will help. So far i have just started it needs alot of more work to be done,girls just read thru my section n leme know wt u think of it. have a nice weekend everyone. Angama.

Hi girls!
Begum, you history info is really good. If very interesting! I really like how you are doing it in order of dates of discovery and what they did, what they found etc! Cant wait to know more.
Angama, your doing well! it sounds like your finding the info hard to get. I'll keep an eye out for you! If your stuck on what you sound be doing then i might have a few ideas. I remember Mark Hill saying that you should compare the genome to the humans genome. so maybe if the genome is the same size as the humans, could you descibe similarities or differences? I know that there is a link to the mouse genome on the mouse web page he gave us ( next to the discussion link). Are you just ment to list the mouse genome sequence? could you go into what genes code what, eg which one codes for the sex linked gene, is it the X and Y gene etc? hopefully Mark gives you some ideas.
well as you might have noticed i've been adding to my stages. the only thing is im worried about there being too much info up there. basically ive tried to get all the info available included in my stages to make sure i cover everything, and then later i'll go over it all and edit and polish it up a bit. Ive done some drawings to the best of my ability, but i can scrap them if you all think they arnt professional enough. just thought i'd try to present the information differently. let me know if you think i'm including too much information. i think i'm having the same problem as you begum, there is lots of info! Elide

Thanks Elide. I'm trying. (Again, loved the artwork!)Btw, Emily, I had a think about your section and I think it might be too much 'clicking' back-and-forth if we link the displayed pic to the 'info' page. Don't stress, you've got the info (heaps which is excellent) but make sure you get some pictures soon so we can start drawing (I'm helping with the drawings as well ok). Mark said 'Nature' and 'Science' have useable images so lets make that our start.
BTW, I will be using the question mark symbol(???) so I don't forget to reference. Begum

Hey everyone, I have found an online text book. it has a chapter on genetics and history and a lot of other stuff. [http://books.google.com.au/books?id=Vt6nUmz1yEQC&pg=RA1-PA207&dq=mouse+development+anatomy&client=firefox-a#v=onepage&q=mouse%20development%20anatomy&f=false] Emily

Hey girls. If you've seen my section, the info is not on the main page, but linked to another page. I thought that it might make everything look more neat. I thought we could all do it like that. It's just an idea. Something different. Maybe we could have something on the main page (picture of a mouse). Your thoughts everybody? Begum

hey begum, ur work looks really good. i like the idea of linking the work to another page. - we don't have to worry about to much info being on the front page and it gives people to option of viewing the work if they want to. ive been working on drawings, i'll show them to you next week but am not sure how to upload them at the moment. Emily

Thanks! That sounds great that you like the idea. About the photos that you are drawing, if there by hand, you can scan them somehow. But overall,
1. click 'Upload File' on the left hand side of this page
2. New page comes up: click 'Browse' and choose your file that you want to upload.
3. Name it (under the Browse button)
NOTE: write down what you named the file as because like Elide says "...it's going to be lost in space!..."
4. Write down info/comments (like who is the author (YOU), and if the drawing is based on a picture)
5. UPLOAD!
6. Go to your section and just normally type this down to the area you want the picture to be seen:
[[image:THE NAME THAT YOU SAVED THE FILE UNDER.jpg|thumb|200px|right|WHAT YOU WANT THE FILE NAME TO VISUALLY COME UP AS]]

Your thoughts Angama and Elide? (about the linking of our sections to separate pages?) Begum.

Oh and another thing:
What do you girls think about my page, I've got a heading for each DATE and underneath each there are further subheadings (e.g. 'What did he do?'. Should I change them to just text, I mean, does it look messy with sub-sub-headings? Begum.

wow girls! great work.. okay so i asked mark about a new page and he said to avoid it because our info is meant to be on our one page. he said if there is extra information on what we wanted to say but is too much for the main page then have a link to our discussion page. (which is what im going to do) Begum your new page is fantastic!! you have done lots of work! but why dont you just put it on our main page? also girls i think we are getting too carried away with info. just keep it simple! i'm sorry i havent been around this week to work on it but i plan to get going asap. just fixing up some things, summarising, writing introductions etc.
did you all read his note about slabbing info onto our page?? how about some introductions, and sentences to ease ourselves into the content. planning on trying to work on that now anyway..

also lets get the information flowing. why dont we go intro, history of model use, stages, timeline, genetics, then current use.. what do you all think?

hey, i thing that that sounds like a good, logical way to do the page. i've finished the drawings, just need to upload them. About the timeline information, is there anything specific that i should include. the stuff that is on the page is a little vague and so i need some advice as to what are key points that i should include. i know that the drawing are very simplistic, let me know wjat you think about them. ive put one up below. i just need a way to link it to text. emily

Thanks Elide. You know, I think that's a great idea. Have it all on one page, seems less 'diverging...', seems more COMPLETE. I love the ORDER as well. I'll fix all that up!

Hey girls, please have a look at what i've done on the timeline. the images are all hand drawn based upon the text: 'the house mouse'. if anyone could give me any ideas on how best to present the pictures - which would be better - next to or below the text? keep in mind that it is incomplete and there is an illustration for each day of development (i.e. 19 in total). if you think that is too many let me know, some may be similar to Elide's ones. Also, do you think i should put some colour into the drawings? Emily

I love your work Emily. All you need to do is put the info on the growth of the mouse that is on the main page, onto the page with the graph of the growth of the mouse embryo...we talked about that before any way-AND I think your parts finished! Begum.
Angama, I added something to the end of your section that I thought was interesting. Have a look. And are you mentioning manipulation and 'shut-down' of the genes in your section?? Begum.
To everyone, apparently ''Mus Musculus'' is the scientific name of the common house mouse, not the mouse. I was thinking of editing that.

HEY EVERYONE! well i've added in some pictures just to make it look more visual, change them if you have better ones.. and i'm going to be working on the current research section tommorow. oh i also added some graphs like we thought of for emilys section.. so i think my section is finished finally! what do you think? can i just say, I think the whole thing looks great! you girls have been a pleasure to work with! :) Thanks so much!!

hi girls, i am sorry..i have been very busy during the mid-sem break and i know we all had our exams and assignments due. but i was having some issues in my family and also the exams and assignments so didnt really had the chance to read wat u girls have got on the main page. i just finished reading thru it and it looks amazing..WELL DONE GIRLS!! you all have done a marvellous job...Eldie and Begum thanks for suggesting some main points to add for the genetics.i am currently working on it.. hopefully tonight i will have all the information on the page..Begum i love how you have presented alot of info into a very easy and understandable way..it makes so much sense..n it looks very nice with the pictures. Eldie and Emily great amount of work and the pictures and the graphs are superb. i just had a look to other groups pages. n i think so far our page looks very interesting with concise info n amazing pictures. n Begum yes i read what you have added thanks for tht..i will cu girls around..gudluck everyone. cheers. Angama.

Girls can you please help me out.. i am so annoyed..
like rite now i was typing some info and when i clicked to save.
it says "conflict" so i think some one else is also editing
the page at the same time that i am. and i lost all my work..arghh..
so which means i have to type it all again.
is there any other way that it tells me that someone else
is also using it so i dont click on save or even preview
because when i do tht i lost all the work tht i had.
If anyone knows please let me know. thanks. Angama.

Current research : I have put some information in the current research part. not sure where they should be put. Begum, as discussed you can edit it or place it in its appropriate place.

Don't stress Angama at all, now you know, it will be over soon. Uploading it easy:

1. click 'Upload File' on the left hand side of this page

2. New page comes up: click 'Browse' and choose your file that you want to upload.

3. Name it (under the Browse button) NOTE: write down what you named the file as because like Elide says "...it's going to be lost in space!..."

4. Write down info/comments (like who is the author (YOU), and if the drawing is based on a picture)

5. UPLOAD! 6. Go to your section and just normally type this down to the area you want the picture to be seen:

It's easier than it is typed! Of you still have problems I will be at the embryo lab, of there is exams there the ANAT LAB opposite to it, if not Level 3 library computers.

[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19538749| maternal diabetes alters transcriptional programs in the developing embryo], [http://www.ncbi.nlm.nih.gov/pubmed/19414407?ordinalpos=35&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum|Abnormal mammary gland development in MMTV-CBLC transgenic mouse], [http://www.ncbi.nlm.nih.gov/pubmed/19394325?ordinalpos=40&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum|Sonic hedgehog signalling inhibits palatogenesis and arrests tooth development in a mouse model of the nevoid basal cell carcinoma syndrome.], [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=55&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum| Fibroblast growth factor 18 gives growth and directional cues to airway cartilage.]

Hi girls, i think i have completed my section. could you all please just read thru it and leme know wat you think of it. i did it to the best of my ability. Hopefully you will all like it if you girls think therez anything more to add or to delete leme know..thanks. gudluck girls. Angama.

Angama your work is fantastic! Thanks so much! im sorry i wasnt around to help you with the problems. hope it went okay. your info is perfect! im very happy with our page! lets hope everyone else is :)

I love it Angama, good work! And the pictures you uploaded are very interesting. Cool. Awesome. Your done!! Begum.

Thanks Begum :) Girls gudluck and cu all tomorrow. Angama.

== Discussion after peer assessment and constructive criticism ==

Hi girls,
Ive started making some changes to the page based on the comments recieved.
Note i've also started a glossary of terms. Also many of our comments regarded our references,so It would be great if we could all reference the same, lets say APA because this is the most common way for referencing. I have gone through our references and tried to format them in APA. many are incomplete references so i have bolded the references that are missing detail. please if you all could complete your references that you added to the list. Also shall we number the references so we can include the numbers in the text as in text references? like foot note? what do you all think... there have been many comments on our current research page.. so how would you all like to fix it? I personally think its way too much. It seems to have accumulated heaps of info from when I last saw it. Is there anyway of summarising the current research info to focus more on how they are used rather than the institute and scientists involved. I think the most important info in this section is what mice are being used to discover currently and proof of the year of study. Cant wait to hear what you all think! Elide

one more thing.. ive tried to edit the contents, as one of our peers suggested, however i cant seem to edit it. do any of you know how to do this?
Elide

hey emily, i see you have reduced the heading in the contents!! thats great! i was just thinking that maybe we dont need so many headings in those 2 sections at all. what do you think about just making all the scientists and the names of people/ labs just in bold.?

Hi girls, have a look at the changes i have made to my section. let me know what you think. Emily

looks good!!
also girls could you please add words from your sections to the glossary, as that whole list is only from the staging section. thanks. elide

Hello girls. I will be re-formatting the history section in order to get rid of the 'gaps' that my peers have mentioned. Also, Elide mentioned yesterday that placing all the 'History' pictures towards the right-side of the page would look more neat, as well as add to the flow of the page. I think this is a great idea. Begum. Oh, and '''what do you guys think about taking out some information (findings)?''' Some students have mentioned that there is too much information/researchers.
And Elide, I'm might change the names of the researchers. like you said before, to bolded text. It would look much more neat. I might, also, '''apply this to the Genetics section. What do you all think?'''

'''Begum's Problem'''
Hey. I placed all pictures to the right-hand side (history section), but the pictures don't correspond well with the text. Any suggestions?? Should I than put the towards the left? Love the change to the timeline section Emily.

HEY BEGUM!!
so your problem.. I dont think the pictures need to match up because if they have a title of the person then the reader can find their picture. plus the comments are on the spaces and gaps between text, not the pictures.. so maybe just put them all underneath each other and even if they dont match up then at least the writing looks more organised. try making the images 200px and not so large and it could work better?. also the bit about taking out the headings in the genetics would be great!! bold would still look fine! goodluck! xox

--[[User:Z3254857|Begum Sonmez]] 14:54, 10 October 2009 (EST) '''TO ELIDE''': I was going to change the headings 'Reproduction' and 'Theiler Stages' under STAGES to bolded text. What do you think? Plus, like you said before, I'm on that ref. list, I will summarise the current research, and change those headings. If the HISTORY pictures match up to the the text, it would be more convenient for the viewer, don't you all think so??? However, the text would appear better the other way with the images al together on the right. Yes, I'll do that.

Hey '''Begum'''!
yes what a great idea about changing the headings in the staging section! the whole page needs to have the same structure throughout! I shall change them right now! :) i'm a little confused about the bit you said about what you said about the ref list. do you mean that you will fix yours? ive been through some of them and looked up the missing details. some are lacking their full reference though. but that would be so great if you could fix up your references. i think the ones in bold are the ones still needing work, but correct the others if you think they arent finished.
well i think the history section looks great! even though the pictures dont match up, they are still there and they look neat and have the same format as the rest of the page. and even better there are no spaces! so it looks great!! i wouldnt worry too much, you've done a such great job providing detail, the pictures are just a bonus!
the reference list looks great! thanks for your help! xox Elide

--[[User:Z3254857|Begum Sonmez]] 20:55, 11 October 2009 (EST)Hello girls! One more thing left: Current Research section. One student said to reduce the number of 'research', but include more information on each. I don't think adding more info under the research is necessary. But '''just keeping the 'breakthroughs'''' would be good, the more important ones. What do you all think? Also, '''what should the headings be''', any suggestion? Should I keep the Organisations as the headings, or the names of the researchers involoved, and/or the dates?

--[[User:Z3224449|Elide Newton]] 11:41, 12 October 2009 (EST) hey. about the current research section. well now that it doesnt have as many spaces and gaps it doesnt look as long, so maybe thats why the student saids to reduce the number of examples. so i'm with you begum, keep the important ones. for example if there are 2 examples of its use in cancer then have only one cancer example. yes headings . i think maybe keep the organisation and date. see what the other girls think.. i'll have a think about it too, and see what we can improve on that section.. overall are we all happy with how its looking? i think its looking great! even the reference list doesnt look messy! :)

== List of things still to do ==
* Check the reference list to see bold references, if these are yours please complete the reference
* formating (remove spaces, make it look neater, make sure the same format is used throughout the whole page)
* add glossary terms
* fix up current research! its really messy!!
* proof read the whole thing
* check if your images have info underneath, reference and copyright liscence.
* remove headings from genetics section

What else do you think needs fixing? these are just some things i know we need to do. Elide xo

== Changes made ==
--[[User:Z3224449|Elide Newton]] 12:17, 2 October 2009 (EST)
*Removed table of stages from discussion page
*Corrected introduction " the mouse has a similar genome to the human"
*In stages section changed size of images to 200px and moved to the right
*Removed spaces and gaps from stages
*Formated stages section to look neater
*Deleted the links to tables on discussion page
*Added in table of theiler stages 12-14 which was on the discussion page
*Started a glossary of terms
--[[User:Z3224449|Elide Newton]] 16:17, 5 October 2009 (EST)
*Added in text citations to the staging section
*Added in more definitions for glossary of terms and referenced glossary
*Went through each reference of reference list and changed the format it into APA, bold for incomplete references.. to note that it needs to be fixed.

--[[User:Z3252340|Emily Wong]] 11:28, 6 October 2009 (EST)
* Edited the contents so that it wasn't as long i.e. took out all the repeated "what did he do?" etcs.
* Edited current research so that contents are not as long. Again taking out the "what did the do" etcs.
--[[User:Z3252340|Emily Wong]] 15:38, 8 October 2009 (EST)
* Edited the timeline of development section by:
** Taking out the written text and incorporated it into the captions below each drawing.
** Rearranging the work so that it was in a better position
** Linked the graph 'Average length of the mouse embryo' into the section by writing a small blurb on it.

--[[User:Z3224449|Elide Newton]] 10:44, 9 October 2009 (EST)
* Removed spaces in sections current research and genetics
* Moved images to the right and changed size to 200px in current research section
* re-uploaded theiler stage 8 image with typo fixed ( reichards to Reicherts)
* added information below images in the staging section.
* added links to source below images in staging section
* deleted 'Photo of mouse vascular development at Theiler stage 20' because I am unable to find copyright liscence
* went through each ref and chagned to APA, had to look up dates and authors for incomplete references added by other students. still some are not complete (in bold) so if you added these references could you please fix.

--[[User:Z3254857|Begum Sonmez]] 12:28, 9 October 2009 (EST)
*Changed the heading 'Chromosome number and banding patterns' under Genetics, from being a main heading to a sub-heading. This was a small mistake that had to be fixed.
*Changed the sub-headings of the history section, that list the years, to bolded text. The reason for this change is that it condensed the amount of headings in the 'Contents', allowing the viewer to have an outline of the page instead of a massive list of each heading. As a result, the page looks more neat, and each section is consistent with eachother.
*Placed all pictures in the History section to the right-side of the page. This is more consistent with the rest of the page, and adds to the flow of the page.
*Placed 2 spaces between each finding, and 1 space between each part of the finding (For example, 'What did they find', 'The Importance'). Again, this is another feature which adds to the consistancy of the page. Many of our peers pointed out that our page was messy. This change helps to solve the problem.

--[[User:Z3224449|Elide Newton]] 20:38, 9 October 2009 (EST)
*Removed headings from current research section and made them bold.
*Finished the glossary of terms from the staging section
*worked on current research. (removed spaces, formated, removed lists of names and added 'et al')

--[[User:Z3254857|Begum Sonmez]] 14:45, 10 October 2009 (EST)
*Changed the sub-headings under the Genetics section to bolded text. There were no complaints about this from our peers. However, since this was applied to the History section, applying it to the Genetics section would be consistent and more neat.
*Placed all HISTORY pictures beneath one another in order to be consistent with the arrangement of other pictures throughout the page.
*Deleted some of the headings (what did they, how did they...) under the history section, as the contents of some of the headings were related. One student mentioned this. As a result, there is less headings, and a greater degree of clarity.
*Edited the Reference list by dividing it into 2 headings ('Books and Articles' and 'Webpage'), and converted some more references into APA style. Just one more conversion left.
*Added the definitions of 'Allophenic', 'Chimera', 'Corpus luteum', 'Somatic tissue' and 'Stem Cell' to the Glossary List.

--[[User:Z3224449|Elide Newton]] 19:44, 10 October 2009 (EST)
*Removed headings from staging section and made bold instead to be the same as the whole page
*Removed two gaps from the genetics section

--[[User:Z3254857|Begum Sonmez]] 14:24, 12 October 2009 (EST)
*Changed some of the Sub-headings under the Current Research section to make it more consistent throughout this section.
*Converted the information under each finding under the Current Research section into numerous small paragraphs because one student outlined that the use of the sub-sub-headings were good at first, but it than became overwhelming. This change enhanced the layout without using the sub-sub-headings and without ending up with a slab of text.

2009 Group Project 4

2009-10-12T03:19:11Z

Z3254857: /* Current Research */

== THE MOUSE (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Are small organisms which can be easily maintained
*Are not expensive
----
===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:Wesley_Whitten.jpg|thumb|200px|right|Wesley K. Whitten]]
[[image:Dame_Anne_Laura_Dorinthea_McLaren.jpg|thumb|200px|right|Dame Anne Laura Dorinthea McLaren]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Beatrice_Mintz.jpg|thumb|200px|right|Beatrice Mintz]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]
[[image:Teruhiko_Wakayama.jpg|thumb|200px|right|Teruhiko Wakayama]]
[[image:Leroy_Stevens.jpg|thumb|200px|right|Leroy Stevens]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Gingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development so far a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development clink the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm.
{{Insert timeline}}
----
===Genetics===
[[image:Genetics_of_laboratory_rodents.jpg|thumb|200px|right|Genetics of labarotory rodents]]

'''Genome'''

Sequencing of the mouse genome was completed in late 2002. Tha haploid genome is about 3 billion long (3000 Mb distributed over 20 chromosomes) and therefore equal to the size of the human genome. The current estimated gene count is 23,786 and humans are estimated to have 23,686 genes.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino (Haldane et al., 1915)
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).

'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome (Laird, 1971). Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.
[[image:Mice_expressing_GFP.jpg|thumb|200px|right|Mice expressing GFP]]
Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function (Hood, 1992). However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

[[image:Figure3-3.jpg‎|thumb|200px|right|Examples of some commonly used mouse strains]]
[[image:Transgenicmouse.jpg|thumb|200px|right|Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition]]
Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]
[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve din mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===
[[image:nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
[[image:NIDCR.jpg|thumb|200px|right|Members of NIDCR]]

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the in organising the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:
1.Supports the multiplication of the H9 cells better than the 3T3 line.
2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: ''An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells''. Link to Abstract [http://www.library.unsw.edu.au/cgi-bin/Data/db.cgi?db=fulltexttest&uid=default&view_records=1&url=http://gateway.proquest.com/openurl?atitle=Harvard+University,+School+of+Medicine;+Human+embryonic+stem+cells+propagated+on+immortalized+drug-resistant+cell+line&date=2006&rft_val_fmt=ori:fmt:kev:mtx:journal&spage=236&issn=1551-529X&ctx_ver=Z39.88-2003&genre=article&res_id=xri:pqd&req_dat=xri:pqil:pq_clntid=&Address=http://gateway.proqu] or [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155) - an Alox5-deficient mouse on a B6 background, and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on mormal HSCs.

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy will be clinically trialed in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia, et al. used the knock out mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knouck out mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cell differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ here].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| Dysplastic histogenesis of cartilage growth plate by alteration of sulphation pathway: a transgenic model] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in critical developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ Maternal diabetes alters transcriptional programs in the developing embryo].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. used the mouse as a model organism to study the epithelial - mesenchymal crosstalk that occurs in Wolffian duct and testis cord development. They found that the epithelial-mesenchymal interactions in the development of these two male structures are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins when mutated become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin rather than the bacterial cell numbers is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab on the mice containing EGFR mutated lung tumors.

It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''' which has been studied to assist in generating antibody and CD4 T helper cell responses.

This process, explained above, was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

{{Template:Projects09}}
[[Category:Mouse]]

2009 Group Project 4

2009-10-12T03:16:12Z

Z3254857: /* Current Research */

== THE MOUSE (''Mus musculus'') ==
[[image:Picture_of_mus_musculus.jpg|thumb|400px|right|Picture of Mouse (Mus Musculus) Wikipedia, 2009]]
=== Introduction ===
The mouse is a small animal which can be used as a model to study embryological development. It belongs to the class of mammalian and order of rodentia and shares a significant similarity in homology with humans. The mouse is one of the most commonly used animals in experimental embryology and most sciences. The mouse is a useful mammalian model for human embryological development because the mouse:
*Has a very similar size genome as the human genome
*Has genes which can be easily manipulated and studied
*Has a high degree of homogeny with humans
*Produces a large offspring in a short amount of time
*Has no ethical issues limiting its use in experiments
*Are small organisms which can be easily maintained
*Are not expensive
----
===History of the use of the Mouse Embryo Model===
'''Introduction'''

The mouse has had a significant contribution to the field of Biomedicine since the middle of the sixteenth century (Hendrich et al. 2004). During the twentieth century, the use of the mouse embryo in particular, has increased significantly, and continues to be a popular experimental choice for researchers.

It's popularity over time in mammalian biology, biomedicine, immunology, oncology, pathology, and genetics is a result of:

*The small size of the mouse and its resistance to infection (Nagy et.al. 2003).
*The efficient mouse breeding system: Which consistently monitors the characterisitcs, that are precisley known, generation after generation, thereby producing highly standardised strains (Hedrich et al. 2004).

*The metabolic and internal anatomical similarities between the mouse and the human, which allows for comparisons. Because of these similarities, they share similar diseases, for example, cancer, diabetes, autoimmunity, endocrine disease, and neurological dysfunctions (Hedrich et al. 2004).

*The ability to manipulate the mouse germ line. This can be achieved by the:

1. Genetic manipulation of embryonic stem (ES) cells, or

2. Direct injection of cloned DNA into zygotes. See ''Genetics'' section below.

Please note that the following findings are based on research which have utilised the model of the mouse embryo.

'''Gregor Johann Mendel (1822-1884), Augustinian priest and scientist'''

[[image:Gregor_Mendel.png|thumb|200px|right|Gregor Johann Mendel]]
[[image:Wesley_Whitten.jpg|thumb|200px|right|Wesley K. Whitten]]
[[image:Dame_Anne_Laura_Dorinthea_McLaren.jpg|thumb|200px|right|Dame Anne Laura Dorinthea McLaren]]
[[image:HOWARD_GREEN.jpg|thumb|200px|right|Dr. Howard Green]]
[[image:Beatrice_Mintz.jpg|thumb|200px|right|Beatrice Mintz]]
[[image:Rudolf_Jaenisch.jpg|thumb|200px|right|Rudolf Jaenisch]]
[[image:Davor_Solter.jpg|thumb|200px|right|Professor Davor Solter]]
[[image:Teruhiko_Wakayama.jpg|thumb|200px|right|Teruhiko Wakayama]]
[[image:Leroy_Stevens.jpg|thumb|200px|right|Leroy Stevens]]

In his notes, ''One Hundred Years of Mouse Genetics: An Intellectual History I The classical period (1902-1980)'', Kenneth Paigen wrote that Mendel's first experiment on the transmission of inheritance was made using mice segregating for coat colour markers. Due to complaints from members of the Catholic Church about the 'smell' of the mice , he changed his material to Pea plants (Hedrich et.al. 2004).

'''1895: Robert Heinrich Johannes Sobotta (1869-1945), German Anatomist [http://translate.google.com.au/translate?hl=en&sl=de&u=http://de.wikipedia.org/wiki/Johannes_Sobotta&ei=6OmdSta8CMWfkQXY4oXiBA&sa=X&oi=translate&resnum=1&ct=result&prev=/search%3Fq%3Djohannes%2Bsobotta%26hl%3Den]'''

'''What did he do?'''
Researched the fertilisation and cleavage of the mouse's egg (Andrews, 1895). Link to Dr. Sobotta's research [http://www.jstor.org/stable/2452637]

'''What did he find?'''
*The corpus Luteum is formed by the enlargement of the epithelial cells of the follicle, aided by growth of connective tissue.
*There is no distinction between corpora lutea vera and corpora lutea spuria.
*The corpora lutea do not degenerate. They remain unchanged during the life of the animal, and therefore add to the size of the ovary.

'''1949: John H. Hammond, Jr. (1888-1965) [http://www.ieee.org/web/aboutus/history_center/biography/hammond.html], Animal Husbandry Scientist'''

'''What did he do?'''

Cultured eight-cell morulae and four-cell-stage mouse embryos to the Blastocyst sage.

This was the first report of successful attempts to culture mouse embryos in vitro to the Blastocyst stage (Nagy et.al. 2003).

The embryos removed at the two-cell stage died a while after (Nagy et.al. 2003).

'''1956: Wesley Kingston Whitten (1918-), Australian Veterinary Scientist'''

'''What did he do?'''

Cultured 8-cell mouse embryos to the Blastocyst stage using a medium containing Krebs-Ringer's bicarbonate solution supplemented with glucose and bovine serum albumin (Nagy et. el. 2003).

Soon after, he found that some two-cell-stage embryos developed into blastocysts, upon some modifications to the original medium.

'''1958: Dame Anne Laura Dorinthea McLaren (1927-2007), Developmental Biologist'''

'''What did she do?'''
Developed the first birth of mice in-vitro. Link to Published article [http://www.nature.com/nature/journal/v182/n4639/abs/182877a0.html]

'''1962: George Todaro (1937-) and Howard Green, Cell Biologists'''

'''What did they do?'''
They studied the fibroblast cells of the mouse embryo in culture.

'''What did they find?'''
:A few weeks after the culture, the growth rate of the Fibroblast cells slowed down. They thought that the cells, as with normal human fibroblast cells, would eventually stop dividing and die. However this was not the case.

:Two to three months later, the cell growth rate increased. This meant that the resulting new population of cells had undergone spontaneous transformation. The resulting permanently dividing cell line, called the '3T3 cell line', have been growing in culture for over 20 years. (Bhamrah et al. 2002)

:As a result, they explained how cells behave in a similar fashion once they have undergone transformation (Bhamrah et al. 2002).

'''1963: Ralph L. Brinster (1932-)[http://www.vet.upenn.edu/FacultyandDepartments/Faculty/tabid/362/Default.aspx?faculty_id=4381375], American Geneticist'''

'''What did he find?'''

*Determined the nutritional requirements of the pre-implantation mouse embryo.
*Established the microdrop technique that allowed two-cell-stage mouse embryos to be cultured to the Blastocyst stage (Nagy et.al. 2003).

'''1965: Beatrice Mintz (1921-)[http://www.bookrags.com/biography/beatrice-mintz/], American Embryologist'''

'''What did she do?'''
Generated adult chimeras.

'''What did she find?'''
The zona pelucida of the mouse embryo could be digested using pronase (Nagy et.al 2003).

'''1974: Rudolf Jaenisch (1942-), German biologist and Beatrice Mintz'''

'''What did they do?'''
Injected purified SV40 (Simian vacuolating virus 40 or Simian virus 40 [http://en.wikipedia.org/wiki/SV40]) DNA into the mouse blastocyst cavity.

'''What did they find?'''
*Viral DNA sequences were detected in the somatic tissue of these mice. Therefore, the DNA had integrated into the genome of embryonic cells (Nagy et.al. 2003).

'''1974: Ralph Brinster [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4610074], & 1975: Mintz and Illmensee [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147], and Papaioannou et al. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1059147]'''

'''What did they find?'''
Embryonic carcinoma (EC) stem cells could be injected into blastocysts to create adult chimeras that contained normal tissues derived from the EC cells.

'''1976: Rudolf Jaenisch'''

'''What did he do?'''
Infected a preimplanted mouse embryo with the Moloney murine leukemia virus. By doing this, he introduced the virus into the mouse germ line in a '''stable''' manner.

The significance of this is outlined below under the findings of Anderson (1980), Capecchi (1980), and Gordon (1980). Overall, Jaenisch's work on the mouse embryo led to the findings of these mentioned researchers.

'''1977: R.J. Mullen'''

'''What did he do?'''
Fused the normal and reeler mouse embryo at the morula stage to produce allophenic mice. (Rouvroit & Goffinet 1998)

'''1980: Ralph L. Brinster'''

'''What did he do?'''
The first to inject purified globin mRNA into mouse zygotes (Nagy et.al. 2003).

This formed the basis for the production of transgenic mice.

'''1980: Wayne F. Anderson, Lydia Killos, L Sanders-Haigh, P J Kretschmer, and E G Diacumakos & 1980: Mario R. Capecchi'''

'''What did they do?'''
Microinjected cloned herpes simplex virus (HSV) thymidine kinase (''tk'') gene into the nuclei of cultured TK-deficient mouse fibroblast cells.

'''What did they find?'''
The incorporation and expression of the ''tk'' gene may be accomplished in a 'stable' manner.

This suggested that the microinjection of DNA into the one-cell mouse embryo might allow for the efficient introduction of cloned genes into the developing mouse (Nagy et.al. 2003). This triggered researchers, including Gordon (mentioned below), to test this possibility.

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6254080/ here] for Anderson's published article, or click [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4C7WJTR-N&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3bc51ea43dcac12e1e879f16f14cd038/ here] for Capecchi's published article.

'''1980: J.W. Gordon, G A Scangos, D J Plotkin, J A Barbosa, and F H Ruddle'''

'''What did they do?'''

Directly injected the cloned HSV thymidine kinase (tk) gene into the pronuclei of zygotes, therefore, introducing the gene into the somatic tissues (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6261253/ here] for Gordon's published article.

'''1981: M.H. Kaufman & M.J. Evans, and 1981: G.R. Martin'''

'''What did they do?'''
They were the first to develop ES cells from cultured mouse blastocysts (Nagy et.al. 2003).

Click [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6950406/ here] for Martin's published article.

'''1983: Davor Solter (1939-), Developmental Biologist'''

'''What did he do?'''
Transferred nuclei between zygotes.

This revealed the importance of parent gene imprinting in mammalian development (Nagy et.al. 2003).

'''1986: Elizabeth Robertson, Allan Bradley, Michael Kuehn & Martin Evans'''

'''What did they do?'''
They were the first to genetically manipulate ES cells (Nagy et.al. 2003).

This allows for the modification and selection of cells with germ-line potential. In turn, this allows them to derive the transgenic strains with pre-determined genetic changes.

By doing this, they inserted many proviral vector sequences that
*Provide new chromosomal molecular markers for linkage studies in the mouse, and
*May cause mutations [http://www.nature.com/nature/journal/v323/n6087/pdf/323445a0.pdf].

'''1996: Toshio Ohshima, Jerrold M. Wardt, Chang-Goo Huht, Glenn Longenecker, Veeranna, Harish C.Pant, Roscoe O. Bradyt, Lee J. Martins, and Ashok B. Kulkarni'''

'''What did they do?'''
Generated Cyclin-dependant kinase 5 (Cdk5) null mice, a type of mutant mice, by homologous recombination to assess the role of Cdk5 in vivo.

Targeted ES cells were injected into blastocysts to generate chimeric mice.

'''1998: Teruhiko Wakayama (1967-), Developmental Biologist and Ryuzo Yanagimachi (1928-), Animal Embryologist'''

'''What did they do?'''
Cloned the first mouse, named Cumulina.

'''1998: Nikola Skreb and colleagues'''

'''What did they find?'''
The early embryonic ectoderm contains cells capable of contributing to all three germ layers of the mouse fetus (Nagy et.al. 2003.

'''Use of teratocarcinomas'''

'''What are teratocarcinomas?'''
They are '...gonadal tumors that contain a...mixture of different tissue types, all derived from a population of undifferentiated stem cells known as embryonal carcinoma cells.' (Nagy et.al. 2003)

The use of teratocarcinomas in research complement the studies on pluripotentiality of cells from the normal embryo and allows for further study of early embryonic development.

'''First pioneered by Leroy Stevens (1920-), Mammalian Embryologist & Barry Pierce'''

Leroy C. Stevens, Jr.:

*The first to identify that male mice of the inbred 129 strain have a low incidence of testicular teratoma arising from primordial germ cells (Link to Stevens and C. C. Little's related article [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16578442]).
*The first to identify modifier genes such as ''ter'' that increase the frequency of teratomas in the testis and eventually developed an inbred strain (129/Sv).
*Developed the LT strain, in which about 50% of females develop ovarian teratocarcinomas.

----

===Staging Of Embryonic Development===

'''Reproduction'''

[[image:Mice_pups.jpg|thumb|200px|right|Picture: Photo of pups of mice Wikipedia 2009]]
Mice can reproduce all year round and are also polyestrous animals, meaning they can breed many times during the year. Male and female mice are capable of breeding at 50 days old and female mice begin their estrous cycle (go on 'heat') between 25-40 days old. The estrous cycle duration is 4-5 days and ovulation occurs spontaneously. A mouse produces an average litter of about 10-12 mice and begins a normal estrous cycle 3-10 days following partuition. Having an understanding of mouse reproduction, can highlight the useful nature of studying the mouse as a mamallian model for human emryology (Greenwald, 1956).

'''Theiler stages'''

Mouse embryonic development commences once the female's egg or oocyte has become fertilized by the male's sperm. Mouse development has a gestation period of 19-21 days, and can range in different strains of mice. The development of an embryo can be categorized into different stages including cell number, somite stages and morphology. The most common method of staging is by Theiler (1989) which categorizes mouse development into prenatal and postnatal stages consisting of 26 and 2 stages respectively. Downs and Davies (1993) have also established a method of staging the mouse development based on morphological changes. Link to Downs and Davies[http://www.ncbi.nlm.nih.gov/pubmed/8269852?dopt=Abstract]
The developmental stages of the mouse embryo can be summarised in the tables and corresponding figures below in relation to characteristics at that stage. The first stage begins with fertiliation of the egg which divides into multiple cells to form a morulla and further go on to form a blastocyst which is ready for implantation (Nagy, et al., 2003).
[[image:Babymouse-1-.jpg|thumb|200px|right|Picture 1: Photo of a one day old mouse Wikipedia 2009]]
[[image:picture 1.JPG|thumb|200px|Figure 1: Illustration of Mouse embryonic stages of development from fertilization to zona free blastocyst (stages 1 to 5). E.Newton 2009]]
[[image:Mouse_theiler_stage8.JPG|thumb|200px|Figure 2: Illustration of Theiler stage 8 (6 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_10.JPG|thumb|200px|Figure 3: Illustration of Theiler stage 10 (7 dpc). E.Newton 2009]]
[[image:Mouse_theiler_stage_11.JPG|thumb|200px|Figure 4: Illustration of Theiler stage 11. E.Newton 2009]]
[[image:Theiler_12.JPG|thumb|200px|right|Figure 4: Illustration of Theiler stage 12. E.Newton 2009]]

{| border='1px'
|+ Table 1: Mouse embryonic stages of development from fertilization to zona free blastocyst, Theiler Stages 1 to 5. (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage !!Embryonic Age in Days Post Coitum (dpc)!!Stage Characteristic !!Cell Characteristics !!Zona Pellucida !!Location !!
|-
|1
|0-0.9
(range 0-0.25)
|One-celled embryo (fertilized)
|One cell
|Present
|Ampulla
|-
|2
|1
(range 1-2.5)
|Dividing egg
|2-4 cells
- 1st cleavage after 24hrs
|Present
|Travelling down oviduct
|-
|3
|2
(range 1-3.5)
|Morula (early to fully compacted)
|4-16 cells
|Present
|Oviduct (utero-tubal junction)
|-
|4
|3
(range 2-4)
|Morula to Blastocyst
-Intra-cellular matrix
-Blastocoelic cavity
|16-40 compacted cells
-Inner cell mass
-Outer layer of trophectoderm cells
|Present
|Uterine lumen
|-
|5
|4
(range 3-5.5)
|Zona free Blastocyst (hatching)
|Blastocyst implants as zona pelludica is lost
|Absent
|Uterine lumen
|-
|}
Once the Blastocyst has lost the zona pellucida, it is free to implant onto the uterine wall.
After implantation multiple features of a trilaminar embryo start to develop. Ectoderm, endoderm and mesoderm layers form, which further develop many structures corresponding to different stages as summariesed in the table below.
The developing mouse embryo which is implanted on the uterine wall can be viewed by ultrasonic radiation. Link to ultrasound of mouse embryo [http://www.youtube.com/watch?v=2_tZHD7iwzQ]

{| border='1px'
|+ Table 2: Mouse embryonic staging from blastocyst implantation to pre-somite formation, Theiler stages 6 to 11(Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
! Theiler Stage !! Embryonic age in Days Post Coitum (dpc) !! Stage Characteristic !! Cell characteristics !!
|-
|6
|4.5 (range 4-5.5)
Human carnegie stage: 4
|Attachment of blastocyst
-Implantation
|Embryonic Endoderm
|-
|7
|5 (range 4.5-6)
Human carnegie stage: 5
|Implantation
-Egg cylinder
-Ectoplacental cone
|Inner cell mass increases
-Epiblast
-Mural trophectoderm lined by endoderm
|-
|8
|6 (range 5-6.5)
Human carnegie stage: 5
|embryonic and extra-embryonic regions
-Pro-amniotic cavity
|Trophoblast giant cells invade
-Maternal blood invades
-Reichert's membrane
|-
|9 a)
|Pre-streak
|Advanced Endometrial and egg cylinder
-Embryonic axis
|Embryonic and extra-embryonic ectoderm
-Uterine crypts lose lumen
|-
|9 b)
|Early streak
|Gastrulation begins
|Mesodermal cells
|-
|10 a)
|7 (range 6.5-7.5)
Mid to late streak
Human carnegie stage: 8
|Amnion formation
|Amniotic fold
-Allantoic bud
-Primitive node
-Amnion closes
|-
|11
|7.5 (range 7.25-8)
Human carnegie stage: 9
|Neural plate and presomites
|Amniotic cavity, exocoelom and ectoplacental cleft
-Allantoic bud elongates
-Notochodal plate
-Early head fold
-Foregut pocket
|-
|}
The next stage (Theiler stage 12) is marked by the first somite pair formation. Stages 13 onwards is characterized by increasing somite pairs up to 20 somite pairs. These embryo stages have characteristic features of developing forgut, prominent head fold, optic pits, branchial arch and neuropore formation. These four stages can be shown in table 3 below.

{| border='1px'
|+ Table 3: Theiler stage 12-14 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler stage !!Embryonic age in Days Post Coitum (dpc) !!Stage characteristic !!Cell characteristics !! Number of somite pairs !!
|-
|12 a)
|8 (range 7.5-8.75)
Human carnegie stage: 9
|Unturned embryo
-1st somite pairs
|Allantois extends into exocoelom
-Maxillary components of 1st brachial arch prominent
-Preotic sulcus
-Cardiogenic plate
-Foregut pocket
|1-4
|-
|12 b)
|8 (range 7.5-8.75)
|Unturned embryo
|Prominent headfolds
-Neural closure
-Optic placodes with optic pits
-Rapid development of heart rudiment
|5-7
|-
|13
|8.5 (range 8-9.25)
Human carnegie stage: 10
|Turning of embryo at around 6-8 pairs
|1st branchial arch with maxillary and mandibular components
-2nd branchial arch visible
- Regionalization of heart visible
-neural tube closure
|8-12
|-
|14
|9 (range 8.5-9.75)
Human carnegie stage: 11
|Anterior neuropore formation and closure
|optic pit indented
-Mandibular process of 1st branchial arch visible
-3rd branchial arch visible
|13-20
|
|-
|}
[[image:Theiler_13.JPG|thumb|200px|Figure 5: Illustration of Theiler stage 12 b). E.Newton 2009]]
[[image:Theiler_13...JPG|thumb|200px|Figure 6: Illustration of Theiler stage 13. E.Newton 2009]]
[[image:Theiler_14.JPG|thumb|200px|Figure 7: Illustration of Theiler stage 14. E.Newton 2009]]
[[image:Chart_of_mouse_development_1.JPG|thumb|200px|Graph 1:Graph of Mouse Development day 1 to 4 dpc. E.Newton 2009]]
[[image:Chart_of_mouse_development_2.JPG|thumb|200px|Graph 2:Graph of Mouse Development of somites. E.Newton 2009]]
Following stage 14, The embryo continues to develop more distinguished features of a mouse, including forelimb and hindlimb bud, tail elongation, lungs and brain development. The stages 15-20 are summarised in the table below.

{| border='1px'
|+Table 4: Mouse embryonic stages from Theiler stage 15 to 20, somite stages (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|15
|9.5 (range 9-10.25)
Human carnegie stage: 12
|Forelimb bud (8-12th somite pair)
-Posterior neuropore
|Hind limb bud
-Telencephalic and diencephalic vesicle division
-Lung development
-Dorsal pancreatic bud
|21-29
|-
|16
|10 (range 9.5-10.75)
Human carnegie stage: 13-15
|Caudal neuropore closes
-Hind limb and tail bud
|Concave 3rd and 4th branchial arches.
-Rathke's pouch
-Nasal processes
-Ventral pancreatic bud
|30-34
|-
|17
|10.5 (range 10-11.25)
Human carnegie stage: 13-15
|Deep Lens Indentation
|Physiological umbilical hernia
-1st branchial arch (maxillary and mandibular components)
-Brain tube development
-Tail elongates
|35-39
|-
|18
|11 (range 10.5-11.25)
Human carnegie stage: 13-15
|Lens Vesicle closes
|Cervical somites not visible
-Brain rapidly grows
-Nasal pit
|40-44
|-
|19
|11.5 (range 11-12.25)
Human carnegie stage: 16
|Lens vesicle separated
–Closed and detached from ectoderm
|Eyes and their peripheral margins
-Limb-girdle and arm
-Anterior footplate.
-Auditory hillocks
|45-47
|-
|20
|12 (range 11.5-13)
Human carnegie stage: 17
|Gingers
|Anterior footplate (develops angles)
-Posterior footplate
-Pigmentation of retina
-Tongue and brain vesicles
|48-51
|-
|}
To visualize the mouse development so far a movie showing the mouse embryo can be seen by following the link [http://www.youtube.com/watch?v=wgYlqgb2V_0]( note the heart beat)
The last few stages of develop (stages 21-26) shown in table 5 are the complete prenatal developmental stages. These stages involve fine development of the pinna over the external acoustic meatus, finger and toe,hair, eyes and whiskers.

{| border='1px'
|+Table 5: Mouse embryonic stages of development Theiler Stages 21-26 (Nagy, et al., 2003; Hill, 2009; Theiler, 1989;)
!Theiler Stage!!Embryonic Age (dpc)!!Stage Characteristic!!Cell Characteristic!! Somite Number(pairs)!!
|-
|21
|13 (range 12.5-14)
Human Carnegie Stage 18-19
|Anterior footplate indented
-Pinna develops
|Digits, elbow and wrist
-5 rows of vibrissae visible
-Hair follicle over eye and ear
-Lens loses lumen
|52-55
|-
|22
|14 (range 13.5-15)
Human Carnegie stage 20-23
|Individual fingers on anterior footplate
-Umbilical hernia visible
|Deep indentations between toes( not separated)
-Long bones of limbs present
-Hair present in pectoral, trunk and pelvis
-Pinna turned forwards
|56-60
|-
|23
|Human fetal period
|Toes separate
|Hair follicles present in cephalic region
-Eyelids open
-Pinna covering ½ of external auditory meatus
|>60
|-
|24
|16
|Reposition of umbilical hernia
|Parallel fingers (2-5)
-Toe nail primordia
-Eyelids fused
-Complete coverage by pinna
-Increase in peritoneal sac size
|>60
|-
|25
|17
|Skin thickened and wrinkled
-Umbilical hernia disappeared
|Subcutaneous veins less visible
-Fingers and toes parallel
-Whiskers visible
|
|-
|26
|18
|Skin thickened
Long whiskers
|Pinna larger (auditory meatus lumen not visible)
|
|-
|}
To view the mouse embryo in late stages of development clink the link [[http://www.youtube.com/watch?v=kieMWaBmNuw]]
Following the prenatal development are the two Theiler stages 27 and 28 which involve birth of the mouse and postnatal development.
----

===Timeline of Development===

[[File:Average length of the mouse embryo.JPG|thumb|200px|right|Average length of the mouse embryo]]

The development of the mouse embryo takes 19 days on average from fertilisation to newborn mouse. In comparison, the human embryo takes on average 40 weeks to progress from the one cell stage to newborn infant. This timing depends on the rate of development of the embryo. The average length of the mouse embryo varies during development depending on what stage the embryo is at and also on the degree of curvature to the body axis. The average length of the newborn embryo is between 23 and 27mm.
{{Insert timeline}}
----
===Genetics===
[[image:Genetics_of_laboratory_rodents.jpg|thumb|200px|right|Genetics of labarotory rodents]]

'''Genome'''

Sequencing of the mouse genome was completed in late 2002. Tha haploid genome is about 3 billion long (3000 Mb distributed over 20 chromosomes) and therefore equal to the size of the human genome. The current estimated gene count is 23,786 and humans are estimated to have 23,686 genes.

'''The genetic map of the mouse'''

Genetic maps, the road maps of genetics, are of two types: linkage and physical. The 'sign posts' on the maps are loci, any location or marker in the genome that can be detected by genetic or DNA analysis. The term 'gene' is more restrictive than loci and refers to DNA segments that encode proteins or can be linked to phenotypes. Linkage maps are recombinational maps and are constructed by carrying out linkage crosses that measure the recombination frequency between genes or loci on the same chromosome.
*The first genetic linkage in the mouse (and first autosomal linkage in mammals) was described in 1915 in the classic paper on the linkage of pink-eyed dilution and albino (Haldane et al., 1915)
*Genetic mapping with spontaneous mutations that created visible phenotypes, such as changes in coat colour/texture or behaviour was labarious and sometimes took years because crosses between mice carrying recessive mutations yielded so few informative progeny, and genes on only one or two chromosomes could be scored in each cross.
*The first real breakthrough in linkage mapping, enabling the scoring of many test markers and chromosomes in the same cross, was the discovery and use of co-dominant biochemical (isoenzyme) genes (e.g. glucose phosphate isomerase 1, Gpil; Hutton and Coleman 1969).

'''How large is the genome?'''

With the use of Feulgen reagent the quantitative DNA-specific staining can be achieved. Through micro photometric measurements of the staining intensity in individual sperm nuclei, it is possible to determine the total amount of DNA present in the haploid mouse genome (Laird, 1971). Measurements indicated a total haploid genome content of 3 pg, which translates into a molecular weight of 1.8 x 1012 daltons (Da).

'''How complex is the genome?'''

Another method for determining genome size relies upon the kinetics of DNA renaturation as a sign of the total content of different DNA sequences in a sample. When a solution of double stranded DNA is denatured into single strands which are then allowed to renature, the time required for renaturation is directly proportional to the complexity of the DNA in the solution, if all other parameters are held constant.

Complexity is a measure of the information contained within the DNA. The maximal information possible in a solution of genomic DNA purified from one animal or tissue culture line is equivalent to the total number of base pairs present in the haploid genome.The information content of a DNA solution is independent of the actual amount or concentration of DNA present. DNA obtained from one million cells of a single animal or cell line contains no more information than the DNA present in one cell. Furthermore, if sequences within the haploid genome are duplicates of one another — repeated sequences — the complexity will drop accordingly.

Renaturation analysis of mouse DNA reveals an overall complexity of approximately 1.3-1.8 x 109 bp. This value is only 40-60% of the size of the complete haploid genome and it implies the existence of a large fraction of repeated sequences.

'''What proportion of the genome is functional?'''

Bacterial species are remarkably efficient at packing the most genetic information into the smallest possible space. In one analysis of a completely sequenced 100 kb region of the E. coli chromosome, it was found that 84% of the total DNA content was actually used to encode polypeptides. Most of the remaining DNA is used for regulatory purposes, and only 2% was found to have no recognizable function.
[[image:Mice_expressing_GFP.jpg|thumb|200px|right|Mice expressing GFP]]
Comparative sequence analysis over long regions of the mouse and human genomes shows evolutionary conservation over stretches of sequence that do not have coding potential or any obvious function (Hood, 1992). However, sequences can only be conserved when selective forces act to maintain their integrity for the benefit of the organism. Thus, conservation implies functionality.The fraction of the mouse genome that is functional is likely to lie somewhere between 5% and 10% of the total DNA present.

'''Chromosome number and banding patterns'''

All of the Mus musculus subspecies have the same standard karyotpye with;
* 20 pairs of chromosomes, including 19 autosomal pairs and the X and Y chromosomes
* All of the 19 autosomes as well as the X and Y chromosome appear to be telocentric, with a centromere at one end and a telomere at the other.
The biological explanation for this uniformity in chromosome morphology is entirely unknown; however, it makes the task of individual chromosome identification much more difficult than it is with human karyotypes.

[[image:Normal_Mus_musculus_karyotype.jpg|thumb|200px|right|Normal Mus musculus karyotype]]

'''Chromosome length and DNA content'''

The amount of DNA present in each chromosome can be estimated by measuring its length — cytologically — relative to the sum of the lengths of all 20 chromosomes and multiplying this fraction by the total genome length of 3,000 mb (Evans, 1989). From these measurements, one finds that the largest chromosome (1) has a DNA length of approximately 216 mb and the smallest chromosome (19) has a DNA length of 81 mb, with all others following in a near-continuum between these two values.

'''Mice with chromosomal aberrations'''

The diploid chromosomal complement of standard inbred laboratory strains is 2N=40:19 autosomes, X and Y chromosomes.The autosomes and the X chromosomes are telocentric (i.e. the centromere is at one end of a single-armed chromosome) while the y chromosome is acrocentric (i.e. it has a short p arm as well as the longer q arm, use of 'p' and 'q' is patterned on human chromosomal nomenclature). The sex determining genes resides in the short arm of the Y chromosome.

Strains of mice whose chromosomal complement devaites from the normal chromosomal makeup are designated chromosomal aberration starins. Chromosomal aberrations can include intra- and interchromosomal rearragements or aneuploidy. These include;

* inversions and transpositions, rearrangements of DNA segments within chromosomes
* reciprocal translocations, Robertsonian chromosomes, and insertions, exchanges of DNA segments between chromosomes
* aneuploidy, deviations from the normal diploid number of chromosomal arms in somatic cells (e.g. trisomies).
Some chromosomal deletions and duplications also may be cytologically detectable.

'''Comparative mapping'''

[[image:Figure3-3.jpg‎|thumb|200px|right|Examples of some commonly used mouse strains]]
[[image:Transgenicmouse.jpg|thumb|200px|right|Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition]]
Comparative mapping began in the early 1970s and gained momentum until it culminated with the sequencing of the two genomes in 2001 and 2002.
* First conserved mouse and human autosomal linkage was reported in 1978.
* 13 conserved autosomal segments and estimated 178(+-)39 chromosomal rearrangements between mouse and human chromosomes were identified (Nadeau and Taylor,1984)
*Sequencing of the two genomes revealed that 95% of the coding sequence is conserved at the DNA level (Consortium,2002)

'''The Knockout Mouse'''

A knockout mouse is a genetically engineered mouse in which one or more genes have been turned off through a gene knockout. They are important animal models for studying the role of genes which have been sequenced. Mice are currently the most closely related laboratory animal species to humans for which the knockout technique can easily be applied.The first knockout mouse was created by Mario R, Capecchi, Martin Evans and Oliver Smilthies in 1989.
[[http://www.youtube.com/watch?v=FEHDGeKMaqY]]

:Use
Knocking out the acitivity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characterisitcs of knockout mice gives researchers information that can be used to better understand how a similar gene may contribute to disease in humans.

:Areas of research in which knockout mice have been useful include:
*cancer
*obesity
*heart disease
*diabetes
*arthritis
*anxiety
*aging
*Parkinson's disease.

:Limitations of the use of Knockout mice
While knockout mice technology represents a valuable research tool, its use may be limited. For example:
*About 15% of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health.
*Knocking out a gene may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. E.g mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.
[[image:Knockoutmouse_picture.jpg|thumb|200px|right|Knockout mice being used as a model for obesity, Wikipedia, 2009]]
[[image:Knockout_mouse_process.JPG|thumb|200px|right| Illustration of the process involved in making a knockout mouse. E.Newton, 2009]]

'''Examples of transgenic models for human diseases''' [[http://www.youtube.com/watch?v=ujZHrR1mro8&feature=related]]

*Models for AIDS study

The HIV-1 virus is known to have two major receptors in human cells CD4 and CCR5. Transgenic rabbits expressing the human CD4 gene were used, the virus replicated in rabbit cells but was unable to generate any disease. Therefore, mouse models were generated. It appeared that transgenic rats expressing all the HIV-1 genes except gag and pol showed pathogeny having many similarities to human AIDS.

*Models for aging

Aging is a complex phenomenon which has only been partially described. Defects in genomes appear to be a major cause of aging. A growing number of trangenic models are being used to study aging. Mice in which the XPD gene has been knocked out are more sensitive to oxidative DNA damage. This sensitivity was increased further when the XPA gene was also knonked out. These models reflect some of the aging syndromes in human.

*Models for Cancer

Transgenic mice are used to generate models for cancer study. The first oncomouse expressed c-myc gene in the mammary gland. This was sufficient to trigger the formation of mammary tumors. Further studies made it pissible to identify additional genes involve din mammary cancer. Genes whose expression is amplified in mammary tumors have an oncogenic effect when used as transgenes. Crossing mice harboring different oncogenes and having knocked out genes has made it possible to determine the cooperative actions of some of these genes.

*The Future

The future of the mouse in genome analysis and as a model organism seems virtually unlimited. Whole genome sequence and gene preditction programs make it quite feasible to knock out or genetically modify every mouse gene. Almost certainly, ES cells will play a key role in future mouse genomics because they can be manipulated in culture. More phenotype screens that can detect mutations prior to making live mice will be needed to increase the number and types of mutations that can be detected in the ES cells themselves. While other model organisms, such as Drosophilia, yeast, worms and zebrafish may be easier to manipulate and allow analysis that require hundreds or thousands of animals, the mouse is likely to continue to be the premier mammalian model for understanding human inherited diseases.

'''International Mouse Strain Resource (IMSR)[http://www.findmice.org//]'''

An on-line database that lists the international availability and supply of inbred, mutant, and genetically engineered mice.
----

===Current Research===
[[image:nude_mouse_pic.jpg|thumb|200px|right|Genetic mutation in gene FOXN1, used in research for tumour grafts and tumours, Wikipedia, 2009]]
[[image:NIDCR.jpg|thumb|200px|right|Members of NIDCR]]

'''Overview'''

Mice are highly used models of developmental biology, immunity, neurobiology, and human diseases in pathology. It's main contribution to developmental biology has been through transgenic and knockout technology which are both very important to the research of early development or organogenesis (Slack, 2006).

'''2003: National Institute of Dental and Craniofacial Research ([http://www.nidcr.nih.gov/ NIDCR])'''

Dr. Ashok Kulkarni and his colleagues created a mouse model of the disease known in humans as ''dentinogenesis imperfecta III''. This heredtitary tooth disorder involves the teeth wearing down to the innermost pulp.

They achieved this by knocking out the dentin sialophosphoprotein (Dspp) mouse gene, thought to be responsible for coordinating the mineralization of a tooth's dentin.

The role of Dspp is to organise the in organising the events during dentin mineralization, including potential regulation of proteoglycan levels. PMID for Dr. Ashok Kulkarni published article: 12721295

'''The International Knockout Mouse Consortium ([http://www.knockoutmouse.org/ IKMC])'''

There goal is to mutate all protein-coding mouse genes using a combination of gene trapping and gene
targeting in mouse embryonic stem (ES) cells.
Programs running under IKMC:
*Knockout Mouse Project (KOMP) (USA)
*European Conditional Mouse Mutagenesis Program (EUCOMM) (Europe)
*North American Conditional Mouse Mutagenesis Project (NorCOMM) (Canada)
*Texas A&M Institute for Genomic Medicine (TIGM) (USA)

'''2006: Green Lab, School of Medicine, Harvard University[http://green.hms.harvard.edu/]'''

Researchers from the Green Lab cultivated Fibroblastic cells of a 12-13 day mouse embryo by 27 consecutive transfers and roughly 63 cell generations. This resulted in a new 'immortalised' cell line called, MMM which:
1.Supports the multiplication of the H9 cells better than the 3T3 line.
2.More effectively maintains the 'immortalised' cells as stem cells.

Link to published article: ''An immortalized drug-resistant cell line established from 12-13 day mouse embryos for the propagation of human embryonic stem cells''. Link to Abstract [http://www.library.unsw.edu.au/cgi-bin/Data/db.cgi?db=fulltexttest&uid=default&view_records=1&url=http://gateway.proquest.com/openurl?atitle=Harvard+University,+School+of+Medicine;+Human+embryonic+stem+cells+propagated+on+immortalized+drug-resistant+cell+line&date=2006&rft_val_fmt=ori:fmt:kev:mtx:journal&spage=236&issn=1551-529X&ctx_ver=Z39.88-2003&genre=article&res_id=xri:pqd&req_dat=xri:pqil:pq_clntid=&Address=http://gateway.proqu] or [http://pt.wkhealth.com/pt/re/diff/abstract.00003444-200604000-00003.htm;jsessionid=KqQdGQpCB70X67D379jLJ2y6ZbCT2TxLP2pLH2LQXnNQgjWXyz23!783167578!181195629!8091!-1]

'''The Jackson Laboratory[http://www.jax.org/index.html]'''

Researchers from The Jackson Laboratory conducted a series of transplantation experiments using three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155) - an Alox5-deficient mouse on a B6 background, and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy").

They found that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs).
At the moment, it is not known why the Alox5 signaling pathway does not have the same effects on mormal HSCs.

Their results demonstrate that targeting a specific gene can completely inhibit only cancer stem cells in vivo.

The efficiency of an anti-stem cell strategy as a cancer therapy will be clinically trialed in order to target ALOX5 in human leukemia patients (The Jackson Laboratory 2009).

'''2009: Department of Experimental Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy'''

Cornaglia, et al. used the knock out mouse to research how mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene caused different forms of the disease chondrodysplasia in humans. By producing a knouck out mice strain of this mutated dtdst gene, they were able to investigate how this gene affected tissue organisation, matrix structure and cell differentiation in the epiphyseal growth plate of the bone.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19637059?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ here].

A Pubmed search of the use of the mouse as a model in the study of embryology was done which produced 5213 literature articles. To view this search please [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pmc&cmd=search&term=embryology%20mouse%20model| click here] . A brief selection of these articles include:

'''2009: Gabriela Pavlinkova, J Michael Salbaum and Claudia Kappen'''

They investigated how maternal diabetes alters transcriptional programs in the developing embryo by using a mouse diabetes model. Maternal diabetes is a known risk factor for abnormalities in the newborn, but it is unknown how this comes about.

They hypothesized that the defects were caused by a change in critical developmental pathways that can result in changes in gene expression. After experimental results were obtained, it was found that exposure to maternal diabetes had caused alterations in the transcriptional profiles of the developing embryo.

Link to published artile: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2715936&tool=pmcentrez&rendertype=abstract/ here].

'''2009: Division of Pediatric Otolaryngology - Head and Neck Surgery at the Cincinnati Children's Hospital, Cincinnati, Ohio'''

Ravindhra et al. hypothesized that the rate and direction of chondrocyte growth was affected by Fibroblast growth factor 18 (FGF18).
To prove this, they used the mouse as a model and observed the affect that FGF18 had on the cartilage specifying gene, Sox9.
There results found that GF18 did regulate the rate and direction of chondrocyte growth by up-regulating Sox9 expression.

Link to published article: [http://www.ncbi.nlm.nih.gov/pubmed/19358209?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum/ Fibroblast growth factor 18 gives growth and directional cues to airway cartilage].

'''2009:Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Illinois & the Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia'''

Denise, et al. used the mouse as a model organism to study the epithelial - mesenchymal crosstalk that occurs in Wolffian duct and testis cord development. They found that the epithelial-mesenchymal interactions in the development of these two male structures are critical for normal development. They were able to identify Inhba and its protein product activin A as being an interstitially derived factor that acts upon sertoli cells in the testis that hints that crosstalk occurs between both organs.

Link to published article: [http://www3.interscience.wiley.com/journal/121496839/abstract?CRETRY=1&SRETRY=0/ Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development].

'''2009: Laboratorio di Biologia Molecolare, Istituto G Gaslini [http://www.gaslini.org/eng/default.asp], Genova, Italy'''

Fardin et al. used the mouse as a model for understanding the function of oncogenes involved in epithelial-mesenchymal uncontrolled growth (Fardin et.al. 2009).

They examined a protein Dbl which belongs to the family of proto-oncogenes or proteins involved in normal cell growth. These proteins when mutated become oncogenes and cause unregulated cell growth. The transgenic mice were used to incorporate the complement DNA strand of Dbl oncogene for analysis.

There results showed that the expression of onco-Dbl in mice correlated with up regulation of epithelial transition, apoptosis, vasculogenesis and cell proliferation.

'''2009: Department of Microbiology and Immunology, University of Maryland School of Medicine[http://medschool.umaryland.edu/microbiology/], Baltimore, MD, USA'''

Andreasen et al. used the mouse as a model of immune response to respiratory tract infections by the bacteria Bordetella pertussis.

They infected the mouse with the bacteria, and found that the mouse secretes a virulence factor called pertussis toxin. This toxin is responsible for promoting bacterial growth and proliferation in the airways.

The study showed that the toxin rather than the bacterial cell numbers is important in the production of cytokine and chemokine responses, and hence the pertussis toxin produces the host immune response not the bacteria.'

'''2009: Regales, et al.'''

They used transgenic mice as models for testing anticancer drugs in lung tumours involved with tyrosine receptor mutations. The lung tumours' mutations were of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutations T790M. By doing this, they were able to evaluate the effectiveness of a variety of anticancer drugs.

In addition, they tested two anticancer agents BIBW-2992 tyrosine kinase inhibitor and EGFR specific antibody cetuximab on the mice containing EGFR mutated lung tumors.

It was found that the combination of the two agents produced marked shrinkage of tumours with T790M mutations.

Link to published article: [http://www.jci.org/articles/view/38746/ Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer].

'''2009: Department of Virology, Statens Serum Institut, Copenhagen, Denmark'''

Gram et al. used mice in the development of HIV-1 vaccines. Note that a vaccine needs to have several factors including several antigens and epitopes, as well as an appropriate adjuvant capable for inducing a strong host cellular immune response.

They used transgenic mice to develop a new lipophillic adjuvant called '''CAF01''' which has been studied to assist in generating antibody and CD4 T helper cell responses.

This process, explained above, was found to generate CD8 T lymphocytes against HIV-1 derived cytotoxic T lymphocyte epitope peptides in human leukocyte antigen mouse models.

Link to published article:[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19759892/ A novel liposome-based adjuvant CAF01 for induction of CD8(+) cytotoxic T-lymphocytes (CTL) to HIV-1 minimal CTL peptides in HLA-A*0201 transgenic mice].

----

== Glossary ==
'''Allantoic bud:''' A sac or diverticulum that prodrudes out from the caudal wall of the umbilical vesicle into the connecting stalk.

'''Allophenic:''' A word used to refer to an animal consisting with a minimum of two genetically-different population of cells originating from different embryos.

'''Amnion:''' A fluid filled sac which encloses the amniotic cavity.

'''Ampulla:''' The dilated end of the Fallopian tube, site of fertilization.

'''Auricular hillocks:''' Embryological bumps which correspond to external ear features in adulthood

'''Blastocyst:''' Structure formed when morula develops a fluid filled space( blastocystic cavity). The balstocyst contains trophoblast and embryoblast cells.

'''Branchial arch:''' Primordial pharyngeal structures, also known as pharyngeal arch

'''Cardiogenic plate:''' Consisting of cardiogenic mesoderm where the heart primordium will develop.

'''Cephalic:''' Term used to describe the head.

'''Chimera:''' An animal consisting with a minimum of two genetically-different population of cells originating from different zygotes.

'''Corpus Luteum:''' The yellowish structure formed as a result of the ruptured graafian follicle that contains cells secreting Progesterone.

'''Diencephalon:''' The third ventricle consisting of 3 swellings which contains the embryonic neural tube region that will form the hypothalmus, thalmus and epithalamus of the brain.

'''Ectoderm:'''One of the 3 germ cell layers, which gives rise to the epidermis, central and peripheral nervous system, ear, eye and neural crest cells.

'''Ectoplacental cone:''' Term describing the polar trophectoderm cell proliferation, of the bastocyst.

'''Endoderm:'''One of the 3 germ cell layers which gives rise to epithelial lining of the respiratory and GIT tract, accessory organs of GIT and lines the yolk sac.

'''Epiblast:''' A thick layer of columnar cells related to the amniotic cavity.

'''Estrous cycle:''' The cycle of female animals which involves the alterations in the female tract as well as sexual receptivity in relation to hormone changes.

'''Exocoelom:''' Term describing the yolk sac, the source of nutrients and cells for the developing embryo.

'''External auditory meatus:''' Also know as ear canal, is the tube from the outer ear to the inner ear.

'''Footplate:''' The paddle shaped structure which forms in the anterior and posterior limb buds to form the hand and foot.

'''Forelimb:''' The anterior limb of an animal.

'''Gastrulation:''' The process in which the three germ layers are developed. These germ layers are the precursors of all embryoni tissue and axial orientation.

'''Genome:''' The total genetic content or genes in an animal.

'''Gestation:''' The period of development from when fertilization occurs or conception until time of birth.

'''Heart rudiment:''' Cone like transitional structure of migrating myocardial precursors which form the primitive heart tube.

'''Hindlimb:''' The posterior limb of an animal.

'''Homology:''' Anatomical structure or traits of two different organisms which resemble similarity from a common ancestral organism.

'''Mesoderm:''' One of the 3 germ cell layers, which gives rise to all skeletal muscles, blood cells and vessel lining, linings of all body cavities, ducts and organs of reporductive system and most of cardiovascular system.

'''Morulla:''' Embryonic structure which consists of 12 to 32 blastomeres.

'''Neural plate:'''Structure when embryonic ectoderm thickens and forms an elongated plate of thickened epithelial cells.

'''Neural tube:''' Structure when neural folds move together and fuse, converting the neural plate into a tube.

'''Neuropore:''' The temporary opening of the neural tube at both rostral and caudal ends of the embryo.

'''Optic pit:''' Depression for optic disc.

'''Optic placode:''' The surface structure of ectoderm thickening in the head region of an early embryo, forms a component of the sensory system of the eye.

'''Ovulation:''' The process of releasing an egg or oocyte from the ovary ( normally midcycle).

'''Pancreatic bud:''' Structure which forms the pancreas between layers of mesentery (dorsal and ventral).

'''Peritoneal sac:'''Space like structure of the peritoneal cavity. Can be divided into greater and lesser sacs.

'''Pinna:''' The external part of the ear. Functions to amplify sound by directing sound waves into the ear.

'''Polyestrous:''' Having many estrous cycles during a breeding season.

'''Postnatal:'''The period of time after birth of a fetus.

'''Prenatal:'''The period of time before birth of a fetus

'''Pre-somites:'''The structure before the appearance of somite pairs.

'''Reicherts membrane:'''A thick basement membrane structure in the parietal wall of the yolk sac.

'''Somatic tissue:''' Tissue that is related to the body of an animal.

'''Somite:''' Mesoderm structure formed from paraxial mesoderm which differentiates to form the sclerotome and dermamyotome. The somites form the muscle and connective tissue.

'''Stem Cell:''' An undifferentiated cell that has the potential to become differentiated. They can retain the ability to divide throughout life.

'''Subcutaneous:'''The soft tissue structure underlying the epidermis or skin.

'''Telencephalon:''' The structure of the embryonic neural tube region which forms the cerebral hemispheres, formed from division of the forebrain.

'''Trophectoderm:'''The cell layer which differentiates to form the trophoblast.

'''Trophoblast:''' Outer cell layer of blastocyst which gives rise to embryonic part of the placenta.

'''Umbilical hernia:'''The outward protrusion of the abdominal lining or part of the abdominal organ at the umbilicus.

'''Vibrissae:'''Follicles of hair also called whiskers.

'''Zona pellucida:'''A specialised zone of cells surrounding the oocyte and blastocyst during early development. Functions in allowing sperm to bind and prevents polyspermy.

(Moore & Persaud, 2008; Biology Online, accessed 2009 [http://www.biology-online.org/])

==References==

<references />

'''Books and Articles'''

*Andreasen, C., Powell, D.A. & Carbonetti, N.H. (2009). Pertussis Toxin Stimulates IL-17 Production in Response to Bordetella pertussis Infection in Mice. ''PLoS ONE'', 4(9), 1-11. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2738961.

*Andrews, E.A. (1895). Embryology. ''The American Naturalist'', 29, 167-169.

*Archambeault, D. R., Tomaszewski, J., Joseph, A., Hinton, B. T., & Yao, H. (2009). Epithelial-mesenchymal crosstalk in Wolffian duct and fetal testis cord development. ''Genesis'', 47(1), 40-48.

*Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., & Davidson, D.R. (1998). An internet accessible database of mouse development anatomy based on a systemic nomenclature. ''Mechanisms of Development'', 74, 111-120.

*Bhamrah, H., & Juneja, K. (2003). ''Molecular Cell Biology 1st edition''. New Delhi. Anmol Publications pp.1-416.

*Cornaglia, A., Casasco, A., Casasco, M., Riva, F., & Necchi, V. (2009). Dysplastic histogenesis of cartilage growth by alteration of sulphation pathway: a transgenic model. ''Connective Tissue Research'', 50(4), 232-42.

*Elluru, R G., Thompson, F., & Reece, A. (2009). Fibroblast Growth Factor 18 Gives Growth and Directional Cues to Airway Cartilage. ''The Laryngoscope Journal'', 199(6), 1154 - 1165. PMID: 19358209.

*Fardin, P., Ognibene, M., & Vanni, C. (2009). Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice. ''PLoS ONE'', 4(9), 1-15. Accessed from, http://assets0.pubget.com/pdf/19759912.pdf

*Ginsburg, M., Snow, M.H., & McLaren, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. ''Development'', 110, 521-528.

*Gram, G.J., Karlsson, I., Agger, E.M., Andersen, P., & Fomsgaard, A. (2009). A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic TLymphocytes(CTL) to HIV-1 Minimal CTL Peptides in HLA-A 0201 Transgenic Mice. ''PLoS ONE'' 4(9), 1-5. Accessed from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2736401

*Greenwald, G. (1956). The Reproductive Cycle of the Field Mouse, Microtus californicus. ''Journal of Mammalogy'', 37(2), 213-222.

*Hedrich, H., Bullock, G., & Petrusz, P. (2004). ''The Laboratory Mouse''. London. Elsevier Academic Press pp.3-24. Accessed from, http://www.google.com/books?id=XLIarRWHikAC&printsec=frontcover&dq=The+laboratory+mouse#v=onepage&q=&f=false

*Hill, M. (2009). The Mouse, UNSW Embryology.''' ISBN: 978 0 7334 2609 4'''. Accessed from http://embryology.med.unsw.edu.au/OtherEmb/mouse1.html

*Moore, K., & Persaud, T. (2008). ''The Developing Human Clinically Oriented Embryology 8th Edition''. Philadelphia. Saunders Elsevier.

*Nagy, A., Gertsenstein, M., Vintersten, K., & Behringer, R. (2003). ''Manipulating the Mouse Embryo: A Laboratory Manual 3rd edition''. New York. Cold Spring Harbor Laboratory Press pp.1-100.

* Pavlinkova, G., Salbaum, J.M. & Kappen, C. (2009). Maternal diabetes alters transcriptional programs in the developing embryo. ''BMC Genomics'', 10(274), 1-12. Accessed from http://www.biomedcentral.com/content/pdf/1471-2164-10-274.pdf

*Regales, Gong, Y., Shen, R., Stanchina, E., Vivanco, I., Goel1, A., Koutcher, J., Spassova, M., Ouerfelli, O., Mellinghoff, I., Zakowski, M., Politi, K., & Pao, W. (2009). Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutation in lung cancer. ''Journal of Clinical Investigation''. Accessed from http://www.jci.org/articles/view/38746

*Rouvroit, C. L., & Goffinet, A. M. (1998). ''Advances in Anatomy, Embryology, and Cell Biology: The Reeler Mouse as a Model of Brain Development''. Berlin. Springer.

*Silver, L. M. (1995). ''Mouse Genetics: Concepts and Applications''. Bar Harbor. Oxford University Press. Accessed from http://www.informatics.jax.org/silver/

*Theiler, K. (1989). ''The House Mouse: Atlas of Embryonic Development''. New York. Springer - Verlag. Accessed from http://genex.hgu.mrc.ac.uk/Databases/Anatomy/new/

'''Websites'''

*'''Bard, J., & Kaufman, M. (2003). The Edinburgh Mouse Atlas Project. ''The Medical Research Council & University of Edinburgh'', Accessed from http://genex.hgu.mrc.ac.uk/Atlas/intro.html'''

*Eye on DNA. ''Image of Transgenic Mouse Embryo Wins Nikon Small World Photomicrography Competition'', retrieved September 24, 2009. http://www.eyeondna.com/2007/10/08/image-of-transgenic-mouse-embryo-wins-nikon-small-world-photomicrography-competition/

*MedicineNet. MedTerms Dictionary, retrieved October 10, 2009. http://www.medterms.com/script/main/hp.asp

*Merriam-Webster Online Medical Dictionary. Retrieved September 23, 2009. http://www.merriam-webster.com/medical/allophenic

*The BioTech Weblog. ''Mouse Resequencing and SNP Discovery Project Completed'', retrieved September 24, 2009. http://www.biotech-weblog.com/50226711/mouse_resequencing_and_snp_discovery_project_completed.php

*The Jackson Laboratory. ''Novel Leukemia Treatment Discovered in Mice'', retrieved September 21, 2009. http://jaxmice.jax.org/news/2009/leukemia.html

*Wikipedia. ''Chimera (genetics)'', retrieved October 10, 2009. http://en.wikipedia.org/wiki/Chimera_(genetics)

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