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2026-09-25T03:53:29Z
User contributions
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https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z5014803&diff=255400
User:Z5014803
2016-10-27T13:59:32Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Student2016}}<br />
<br />
==Lab Attendance==<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 18:29, 5 August 2016 (AEST)<br />
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[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:40, 12 August 2016 (AEST)<br />
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[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:07, 19 August 2016 (AEST)<br />
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[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:09, 26 August 2016 (AEST)<br />
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[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:45, 2 September 2016 (AEST)<br />
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[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:13, 9 September 2016 (AEST)<br />
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[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:46, 23 September 2016 (AEST)<br />
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[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:58, 7 October 2016 (AEDT)<br />
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<br />
===Belbin Team Roles===<br />
In my previous courses, I was introduced to the Bebin model team roles as a way to identify myself in a team scenario. I definitely see myself as a "Shaper" since I am driven to try and complete the task at hand as soon as possible to ensure sufficient time for the editing process and the refining of the task. I also agree that I motivate other team members to progress through the task at a efficient pace such that the group does not lose momentum. I am also a person who is not afraid to speak my mind and thus will contest other viewpoints in order to spark a discussion. I identify myself as a very dynamic person in the way that I act according to the different predicaments I'm in and this results in numerous ways of efficiently solving any problems. Although I identify myself as a Shape I do not agree that i can become aggressive or bad humoured as I see some traits of a Co-ordinator in me. I have a very mature approach and recognise that each individual has a different way of attacking a problem and have learnt to appreciate others. <br />
<br />
===Lecture 1: Fertilisation===<br />
I have always been fond of the details surrounding fertilisation as it seems like a very interesting topic. It is more than just a sperm and egg cell coming together. The first lecture on fertilisation highlighted the various processes that need to occur in order to form a zygote, from gametogenesis to fertilisation and then forming the zygote. In my first year studies I learnt that there is a mechanism to prevent multiple sperm cells to enter the ovum but wasnt familiar with the process. The most interesting aspect of this lecture was precisely the process from fertilisation to the prevention of polyspermy. I was intrigued by how sperm cells are attracted to the oocyte which was through the ZP2 protein and only the nucleus of the spermatozoa enters the cell membranes. I was also interested in how membrane fusion will result in oocyte processes that will prevent polyspermy through the elevation of intracellular calcium levels. I had minimal knowledge of this topic but the lecture really made me want to learn about this process in a lot more detail.<br />
<br />
==New SubHeading==<br />
===External Link===<br />
[http://www.smh.com.au/ SMH]<br />
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===Internal Link===<br />
[[ANAT2341 Lab 1]]<br />
<br />
[[ANAT2341 Lab 1|Fertilization Lab]]<br />
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[[Student Page]]<br />
<br />
==Referencing==<br />
[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=fertilization fertilization]<br />
<br />
PMID 27486480<br />
<br />
==Assessment 1==<br />
<br />
<pubmed>27486266</pubmed> <br />
<br />
In order for fertilization to occur spermatozoa must be activated in a process known as 'sperm capacitation'. The primary research article "Seminal vesicle proteins SVS3 and SVS4 facilitate SVS2 effect on sperm capacitation" by Araki et al (2016) investigate the role of seminal vesicle secretion and how they inhibit the activation of spermatozoa and how they reduce the fertility of the capacitated spermatozoa (decapacitation). In previous studies it has already been shown that SVS2 acts as a capacitation inhibitor and a decapacitation factor and Araki et al (2016) build up on this pre existent knowledge about SVSs other than SVS2. The investigation utilised CD-1 mice, in particular female mice, to show the effects of SVS3 and SVS4 on sperm cells in the female reproductive tract. <br />
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<br />
Levels of SVS3 and SVS4 were measured in each part of the female reproductive tract such as the copulaatory plug, vagina, oviduct and uterine region near the vagina and oviduct 1.5 hours post copulation. By using anti SVS3 antibody there were clear indications as to the specific roles of SVS3. Results showed that there were no SVS3 proteins in any of the aforementioned parts of the reproductive tract and thus the protein alone had no effects on sperm capacitation. In saying that, SVS3 proteins did show that they had the ability to potentiate the effects of SVS2. Similarly anti SVS4 antibody was utilised to provide insight into the function of this particular protein. Contrary to the findings for SVS3, SVS4 was detected in the uterus but not in any other part of the tract. This suggests that SVS4 has similar activity to that of SVS2 in a way that both the proteins enter the uterus. Thus, SVS4 acts as a capacitation inhibitor similar to SVS2 but results indicated that it does not have the decapacitation effect like SVS2.<br />
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{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 18 August 2016 - You have added the citation correctly and written a good summary of this very recent article, still only available in the pre-published submitted format, findings. One thing, you must always include the full term in your summary (even if it appears in the paper title) before you begin to use the acronym. "SVS" (seminal vesicle protein secretion) could and may mean different things in different contexts.<br />
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| width=100px| Assessment 5/5<br />
|}<br />
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==Assessment 2==<br />
<br />
[[File:Development_of_mouse_embryo_in_early_stages.png|400px|thumb|centre|Live imaging of the whole mouse embryo at E6 (A to D) and E5.5. (E to H)<ref><pubmed>23861733</pubmed></ref>]]<br />
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{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 29 August 2016 - Reference and Copyright correctly included with the file and referenced on your page here. You have not included the <nowiki>{{Student Image}}</nowiki> template in the file summary box.<br />
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| Assessment 4.5/5<br />
|}<br />
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===References===<br />
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== Lab 3 Assessment ==<br />
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{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 31 August 2016 - Lab 3 Assessment Quiz - [[Lecture_-_Mesoderm_Development|Mesoderm]] and [[Lecture_-_Ectoderm_Development|Ectoderm]] development. All correct, Well done!<br />
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| Assessment 5/5<br />
|}<br />
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<br />
==Assessment 4==<br />
==Quiz==<br />
<br />
<quiz display=simple><br />
<br />
{Which of the following structures does the ectoderm contribute to?<br />
|type="()"}<br />
- epithelium, mesentry, connective tissue<br />
+ enteric nervous system<br />
- epithelium and smooth muscle<br />
- enteric nervous system, connective tissue, smooth muscle<br />
|| Option two is correct as the ectoderm only contributes to the enteric nervous system. Epithelium is contributed by the endoderm, whereas the mesentry, connective tissues, smooth muscle, blood vessels are contributed by the mesoderm<br />
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{What lies rostral in relation to the notochord?<br />
|type="()"}<br />
- mesoderm<br />
- the neural tube<br />
+ the buccopharyngeal membrane<br />
- the mesoderm then endoderm<br />
|| The buccopharyngeal membrane lies rostral in relation to the notochord. The mesoderm lies laterally to the notochord, the neural tube dorsally and the mesoderm and endoderm ventrally.<br />
<br />
{During Week 8- 10 (GA 10- 12 weeks):<br />
|type="()"}<br />
+ neural crest migrates into the wall forms enteric nervous system<br />
- endoderm in the GIT wall proliferates<br />
- a second rotation (of 90 degrees) occurs on the longitudinal axis establishing the adult orientation of the stomach.<br />
- mesoderm within the dorsal mesogastrium form a long strip of cells adjacent to the forming stomach above the developing pancreas<br />
|| Option A is correct and is the only one that occurs during weeks 8-10. Option B occurs at the beginning of Week 5. Option C occurs during Week 4. Option D also occurs in Week 5 and is incorrect<br />
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{Narrowing of a lumen such as the duodenum or the pylorus is also called:<br />
|type="()"}<br />
- duplication<br />
- atresia.<br />
+ stenosis<br />
- gastroschisis<br />
|| Stenosis is the correct answer. Duplication is the incomplete recanalization resulting in parallel lumens, this is really a specialized form of stenosis. Atresia is the interuption of the lumen and gastroschisis is a congenital abdominal wall defect which results in herniation of fetal abdominal viscera into the amniotic cavity.<br />
<br />
</quiz><br />
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{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 13 October 2016 - These seem good quiz questions. Question 1 should have been worded "Which of the following GIT structures". The other questions and your answers are fine.<br />
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| Assessment 5/5<br />
|}<br />
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[[Student Page]]<br />
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==Lab 6 Assessment==<br />
<br />
Completed ANAT2341 Lab 5 - Course Feedback Questionnaire<br />
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{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 11 October 2016 - Questionnaire on course structure.<br />
| Assessment 5/5<br />
|}<br />
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==Lab 6 Assessment==<br />
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===Identify a known genetic mutation that is associated with cleft lip or palate===<br />
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Tbx22 mutations are associated with cleft lip/palate<br />
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===Identify a recent research article on this gene===<br />
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[https://www.ncbi.nlm.nih.gov/pubmed/21375406 Arunee Kaewkhampa, D.D.S., M.S., Dhirawat Jotikasthira, D.D.S., M.S., Sutti Malaivijitnond, D.D.S., M.S.,<br />
Piranit Kantaputra, D.D.S., M.S '''TBX22 Mutation Associated With Cleft Lip/Palate, Hypodontia, and Limb Anomaly''' Cleft Palate Craniofacial Journal.: 2012, 49(2); 240-4 PubMed 21375406]<br />
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===How does this mutation affect developmental signalling in normal development===<br />
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{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 13 October 2016 - This assessment is incomplete.<br />
| Assessment 2/5<br />
|}<br />
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==Lab 7 Assessment==<br />
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===Muscular Dystrophy===<br />
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'''''What is/are the dystrophin mutation(s)?'''''<br />
<br />
The mutations in the dystrophin gene can sequentially lead to two types of muscular dystrophies; Duchene (DMD) and Becker (BMD) muscular dystrophy. DMD is the largest known gene in humans measuring 2.4Mb. The gene provides the coding for the a protein called dystrophin which is located primarily in muscles (skeletal and cardiac) and in minor quantities in nerve cells. In most cases mutations in this gene are of the deletion type in which pieces of DNA are lost. Other types of mutations include large duplications (pieces of DNA are copied) and point mutations (small changes in the DNA code). The aforementioned dystrophies arise from deletions in the dystrophin gene. <br />
<ref name="PMID23961084 "><pubmed>23961084</pubmed></ref><br />
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'''''What is the function of dystrophin?'''''<br />
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The dystrophin protein provides a structural link between the cytoskeleton of muscles and the extracellular matrix which attributes to maintaining the muscle integrity. It is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Although not much is known about the protein it is thought to cause membrane stabilisation and a lack of the protein can activate multiple pathophysiological processes. <br />
<ref name="PMID11917091"><pubmed>11917091</pubmed></ref><br />
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'''''What other tissues/organs are affected by this disorder?'''''<br />
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A gradual deterioration in lung function occurs as respiratory muscles weaken resulting in respiratory failure. The heart can also be affected in 1 of 2 ways namely abnormal heart rhythms and cardiomyopathy. <br />
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'''''What therapies exist for DMD?'''''<br />
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There is no cure for the disease as of yet but there are various research programs worldwide tackling this issue. There are also measures that can help manage the condition and improve quality of life. These include exercise, supportive environment, medical treatment (steroid treatment mostly), nutrition, surgeries, and palliative care. Other therapies that are currently under going research include gene therapy, reading through stop signals, stem cell therapy, utrophin upregulation, moosting muscle growth and reducing muscle damage<br />
<ref name="PMID22533379"><pubmed>22533379</pubmed></ref> <br />
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'''''What animal models are available for muscular dystrophy?'''''<br />
<br />
The mouse is used animal model for muscular dystrophy. Other animal that have been utilised include the golden retriever dog and pigs. <br />
<ref name="PMID22137430"><pubmed>22137430</pubmed></ref><br />
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{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 13 October 2016 - These are good responses including referencing.<br />
| Assessment 5/5<br />
|}<br />
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=<u>Lab 9 Peer Review</u>=<br />
<br><br />
<font size="4"><u>Group 1:</u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br><br />
Upon initially glancing over the project you can clearly see a range on headings and subheadings and it is evident by these that the project is about the WnT signalling pathway in skin of fetus. This is sufficient for assessment criteria 1 and 2 as you can see the aspect of research they are targeting such as skin formation during embryonic development. Throughout the text you can see citations relating to the topic and a range of references at the end of the project. This satisfies the requirements for criteria 3 but just a small critique would be to put these references in the references section just to clear out the unnecessary area. It can also be commended that the group project goes above and beyond the curriculum of informing us about the background information of WnT signalling pathway in skin of fetus but also includes the complications and diseases arising due to abnormalities in the WnT pathway. This is excellent and satisfies the requirements for criteria 5<br />
<br><br />
<br><br />
There can be some improvements in the project but they are not necessarily of the utmost importance. Firstly, the group can add other specific subheadings and the relevant information under them such as the history or background of the signalling pathway. This is just so the reader has a more rounded knowledge of the pathway and can increase the interest and keep them engaged. It would also be good to see in the text and not just at the end of a paragraph. Such as, in the canonical and non canonical pathway heading it would be recommended to have in text citation and not just at the end just to show the reader where the information was gathered from.<br />
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<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Although the project has a fair amount of positives there are some areas that are lacking. Firstly, the report requires additional information in each section and how this information can be linked to pathways in embryological development. It would also be recommended to put in diagrams, images, tables etc. This would engage the reader and make the read more interesting since at the moment there are no images or tables. Also doing so will satisfy one aspect of criteria 2. This way the audience can develop a visual understanding of the topic. It would be advisable to put tables in the history section in the form of relevant dates/years and the information corresponding to the year. <br />
<br><br />
<br><br />
Also, it would be good to see the role of WnT signalling pathway in something other than skin, for eg: an organ or tissue or cell. This would aid in achieving a higher mark for criteria 5 as you go above the required information. Overall it was great to see all group members contributing to the project but minor edits such as citations, images, tables, and adding additional information to sections would really captivate the reader and make it an enjoyable read. <br />
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<font size="4"><u>Group 3:</u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements: </b><br />
<br><br />
<br><br />
The group project looks terrific at the initial glance. You can clearly see all the headings and subheadings. In particular, it is great to see a range of subheadings such as “limb bud formation”, “bone development”, “kidney development”. This shows that there was a lot of research put into this project. Also by doing so you have made it clear that your project is about the Fibroblast Growth Factor Receptor Pathway (FGFR). The page is also very easy to navigate as well which was nice to see. <br />
<br><br />
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It is also great to see that there is addition of tables, images, and diagrams as it kept the read a lot more interesting and captivating. This allowed you to successfully satisfy criteria 2. It is also good to see correct in text citations and references as this allowed the reader to search for additional information if interested or necessary. Although you haven’t made up any multiple choice questions it is excellent to see a MCQ section. This is a great way to test the readers’ knowledge and in turn you can reflect if you have provided accurate and sufficient information to answer these questions. <br />
<br><br />
<br><br />
It was great to see that you added an abnormalities section and in particular different types of syndromes and disorders. This meant that you went over the minimum information required and put in extra effort to create a coherent project. This satisfied criteria 5 and thus a better project. Overall there are many positives in this report and with minor amendments such as adding information to sections such as “Apert syndrome”, “Animal models”, “Kidney development”, “external genitalia development” etc, a very articulate and well rounded project will be created.<br />
<br><br />
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<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Although there are many positives in the project, there should be some amendments to the project just to ensure all bases are covered. Firstly, it would be advised to increase the amount of information to the introduction and history sections. As these sections are lacking information, the reader may not have enough information to carry on reading as their base on this topic isn’t really strong and lacks information. This can easily turn off new readers and inhibit further exploration of the topic/ project. By adding additional dates in the history section, a better overall knowledge and background of the signalling pathway can be developed which can only enhance learning. <br />
<br><br />
<br><br />
Overall, there are not many negatives and I believe as a reader your project was a great example of progress so far and with the aforementioned minor tweaks, your group is well on their way to achieving extremely high marks. <br />
<br><br />
<br><br />
<font size="4"><u>Group 4:</u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
At initial glance I can see a range of headings and subheadings which just made it easier to navigate from one aspect of the project to another. This satisfied the requirements for criteria 1 and 2. This also allowed me to recognise the main topic of the project is the Hedgehog signalling pathway. There is also an addition of an image of the pathway which was great to see as it outlines the main components of the pathway and in general educates the reader about the signalling pathway. This provided a visual stimulus/ description which in turn engaged the reader to find out more about the topic.<br />
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It was also good to see correct in text citations and a references list at the end which in turn satisfied criteria 3. To satisfy criteria 5 it was excellent to see information that was well beyond the required information. An example of this is when discussing the role of the pathway in not only humans but also in mice, chicks and fruit flies. The group also began to include new research and abnormalities related to the Shh pathway which aided in rounding off criteria 1. <br />
<br><br />
<br><br />
In order to improve the already positives of this project it would be advised to add a description to the image just so the reader can have some sort of summary about the main points of the image/ pathway. Also, addition of diagrams or tables in some of the subheadings would be good as it will keep the reader interested and in general provide a visual aid. Also it is necessary to cite and provide a reference of the image as it breaches the copyright laws. <br />
<br><br />
<br><br />
<b>Negative aspects of the project and suggested improvements: </b><br />
<br><br />
<br><br />
Although there are positives to the project, there are a few negatives that can easily be fixed. It is crucial to put in an “Introduction” heading and providing relevant information. This in turn will create a coherent project as it flows from one aspect to another whilst simultaneously providing a brief overview of the Sonic Hedgehog Pathway. Although you have explored the mechanism in animal models it is imperative to link this to embryological development. Also, addition of diagrams, interactive quizzes and tables is necessary to satisfy criteria 3, since 1 image is not enough. <br />
<br><br />
<br><br />
Adding a glossary of terms at the end of the project is needed to clarify any words or phrases that have not been previously encountered such as “organogenesis”, “paracrine”, “dephosphorylation” etc. Overall, the project is coming along nicely and with the recommended amendments, a high mark is definitely in order. <br />
<br><br />
<br><br />
<font size="4"><u>Group 5: </u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Upon reviewing the page, it is evident that there has been a lot of research put in this project. Initially, there is evidence of a range of headings and subheadings which allowed the navigation from one aspect of the project to another extremely easy. This allowed me to confirm that the project is about T-box genes and their signalling. Secondly, it was excellent to see a range of images, tables and graphs as they provided visual aids to learn more about the topic and in general made it easier to accumulate information. Also it was good to see that these tables and images were correctly cited and referenced at the end which meant that there was no breach of copyright laws. <br />
<br><br />
<br><br />
Also, throughout the project there was sufficient amount of information in each subheading which meant that the reader gained all relevant information pertaining to the section that they are reading. It was also great to see a range of abnormalities being added to the project. This meant that you have went above and beyond the scope of the assessment and researched that extra bit to provide additional information about the signalling pathway and complications arising from any mutations. This meant that you successfully satisfied criteria 5 and thus a more rounded project. <br />
<br><br />
<br><br />
<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
This project certainly contains a range of positives but there were minimal negatives that can easily be amended in order to achieve a very high mark. I noticed that there was more than 1 image being used from Wikipedia and the criterion clearly says that a maximum of 1 was allowed. This is not a big deal but just in case there is harsh marking and penalties, it is advised to replace the additional image with another image. In addition, it would be useful to add a glossary of all the terms that one may find confusing such as “homologues”, “heterozygous”, “homology”, “notochord” etc. This in turn will provide the reader with enough information to understand the context of the project and in turn keep them engaged.<br />
<br><br />
<br><br />
Another negative aspect of the project was that the subheading “Ancient origins and evolution of the T-box gene family” randomly appearing nearing the end of the project. This looked a bit out of place and not flowing with the rest of the passage. To correct this it would be advised to add this to the start of the page with the “Origin of the T-box genes” section just so the information clearly flows from one topic to another without creating confusion. Overall, this project is coming along quite nicely. It is evident that a lot of research has been put into constructing a coherent and succinct project but also have the visual cues to back up the main aspects. To maximise marks, it is recommended to reflect on the feedback and correct the minor mistakes. <br />
<br><br />
<br><br />
<font size="4"><u>Group 6:</u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Upon reviewing the page I can see a number of headings and subheadings such as the nature of the growth factor, its mechanism of action, history and emerging research. But to be critical, a range of other headings is necessary to ensure all bases are covered when researching and providing the relevant information. This will help in satisfying the requirements for criteria 1 and 2. It is good to see the addition of a diagram to your project as it is a requirement for criteria 2. This provided a visual aid that kept me interested to find out more about the topic while simultaneously making it easier to understand the theory behind the process of TGF Beta signalling pathway. It is also great to see the current research and limitations as this shows that you are going beyond the scope of the required criteria and researching ahead to provide that extra bit of information. This in turn is a great way to satisfy criteria 5.<br />
<br><br />
<br><br />
<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Although there are a few positives in the project, there are a number of negatives which can be improved upon to ensure a coherent project is created. Firstly, it is advised to put the heading “history of TGF- beta signalling pathway at the top” with the introduction as this is an introductory section and should be addressed initially on the page. This will allow you to create a more flowing page which also looks nice. Secondly, it would be advised to add more images and tables as it is a requirement for criteria 2. By doing this you will keep the reader engaged and wanting to find out more about the chosen topic. In saying that, you already have a couple of images but not referenced. It is imperative to correctly cite and reference these images as failure to do so will result in a breach of copyright laws. <br />
<br><br />
<br><br />
Another critique is to add more subheadings with a range of different aspects of the signalling pathway being explored. It is recommended that you dedicate a chunk of your project to describing the pathway in detail and its role in embryonic development and abnormalities relating to mutations caused by the pathway. This will ensure you answer criteria 6 as it is a great deal of the report. It is also advised to put the history section under the introduction section as placing it in the middle of the project is a bit out of place and inhibits the flow of the information from one subheading to another. Also, the history section can be improved by adding more information as there have been more findings in this research topic since the 1970s. An addition of glossary is also needed for terms such as “peptide”, “cytokine”, “angiogenesis”, “protein kinase” etc. This will aid readers understand terms that they previously have not encountered and allow them to correctly understand the context of the information. <br />
<br><br />
<br><br />
It has also come to my attention that there are little to no references or in text citations. By adding information without correctly giving the authors credit is a breach of copyright laws and must be done urgently. Overall, the project shows signs of progress with a number of positives. By reflecting on the negative aspects and acting upon it, it is certain that high marks are in order.<br />
<br />
<br />
{{Stem Cell Presentations 2016}}<br />
<br />
<br />
<br />
==Lab 11 Assessment==<br />
<br />
Ischemic myocardial infarction causes irreversible cell loss and scarring and is a major source of morbidity and mortality in humans. Thus, the inability to replace damaged cardiac muscle ranks among the most prominent regenerative failures of mammals. The investigation by Lepilina et al studied Zebrafish, an animal with a unique yet poorly understood capacity for cardiac regeneration. Their results indicated that the regeneration of the myocardium occurs through 2 coordinated stages after the resection of the ventricular apex. Initially, a blastema is formed, a mass of cells capable of growth and regeneration into organs or body parts. They are comprised of progenitor cells that express precardiac markers and undergo differentiation and proliferation. In the second stage, the tissue surrounding both cardiac chambers induces developmental markers and exponentially expands. This creates a new epithelium cover for the underlying exposed myocardium. New vasculature then forms supplying the regeneration muscle by epicardial cells invading the wound. These cells undergo epithelial-to-mesenchymal transition (EMT). The fibroblast growth factor of subtype 17 b (fgf17b) in induced in the myocardium in the regenerative phase whereas the receptors fgfr2 and fgfr4 are induced in neighbouring epicardial derived cells. The investigation revealed that injury to the myocardium or the epicardial tissue collaborate in an Fgf-dependent manner to achieve cardiac regeneration.<br />
<br />
This primary article is related to the review article in several ways. Since adult myocardium is prone to scarring and hypertrophy leading to fatal arrythmias and heart failure, cardiac regeneration in mammals (especially humans) shows low proliferative capacity. This is juxtaposed in the review article by relating it to the mechanisms in the zebrafish, which shows that they can in fact regenerate cardiac muscle after injury, suggesting that latent regenerative potential exists. The review article also draws differences in the inability of mammals to regenerate crucial structures, including limbs, spinal cord and cardiac muscle. However, zebrafish etain the ability to regenerate these and other organs. Thus there is some significance as to how such animals have these fundamental aspects in relation to cardiac regeneration and their ability to repair themselves efficiently. Thus the primary research article provides an understanding of the processes and mechanisms that help certain species to allow proliferation of cardiomyocytes which can aid in generating new targets for therapeutic manipulation.</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z5014803&diff=255398
User:Z5014803
2016-10-27T13:58:26Z
<p>Z5014803: /* Lab 11 Assessment */</p>
<hr />
<div>{{ANAT2341Student2016}}<br />
<br />
==Lab Attendance==<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 18:29, 5 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:40, 12 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:07, 19 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:09, 26 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:45, 2 September 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:13, 9 September 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:46, 23 September 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:58, 7 October 2016 (AEDT)<br />
<br />
<br />
===Belbin Team Roles===<br />
In my previous courses, I was introduced to the Bebin model team roles as a way to identify myself in a team scenario. I definitely see myself as a "Shaper" since I am driven to try and complete the task at hand as soon as possible to ensure sufficient time for the editing process and the refining of the task. I also agree that I motivate other team members to progress through the task at a efficient pace such that the group does not lose momentum. I am also a person who is not afraid to speak my mind and thus will contest other viewpoints in order to spark a discussion. I identify myself as a very dynamic person in the way that I act according to the different predicaments I'm in and this results in numerous ways of efficiently solving any problems. Although I identify myself as a Shape I do not agree that i can become aggressive or bad humoured as I see some traits of a Co-ordinator in me. I have a very mature approach and recognise that each individual has a different way of attacking a problem and have learnt to appreciate others. <br />
<br />
===Lecture 1: Fertilisation===<br />
I have always been fond of the details surrounding fertilisation as it seems like a very interesting topic. It is more than just a sperm and egg cell coming together. The first lecture on fertilisation highlighted the various processes that need to occur in order to form a zygote, from gametogenesis to fertilisation and then forming the zygote. In my first year studies I learnt that there is a mechanism to prevent multiple sperm cells to enter the ovum but wasnt familiar with the process. The most interesting aspect of this lecture was precisely the process from fertilisation to the prevention of polyspermy. I was intrigued by how sperm cells are attracted to the oocyte which was through the ZP2 protein and only the nucleus of the spermatozoa enters the cell membranes. I was also interested in how membrane fusion will result in oocyte processes that will prevent polyspermy through the elevation of intracellular calcium levels. I had minimal knowledge of this topic but the lecture really made me want to learn about this process in a lot more detail.<br />
<br />
==New SubHeading==<br />
===External Link===<br />
[http://www.smh.com.au/ SMH]<br />
<br />
===Internal Link===<br />
[[ANAT2341 Lab 1]]<br />
<br />
[[ANAT2341 Lab 1|Fertilization Lab]]<br />
<br />
[[Student Page]]<br />
<br />
==Referencing==<br />
[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=fertilization fertilization]<br />
<br />
PMID 27486480<br />
<br />
==Assessment 1==<br />
<br />
<pubmed>27486266</pubmed> <br />
<br />
In order for fertilization to occur spermatozoa must be activated in a process known as 'sperm capacitation'. The primary research article "Seminal vesicle proteins SVS3 and SVS4 facilitate SVS2 effect on sperm capacitation" by Araki et al (2016) investigate the role of seminal vesicle secretion and how they inhibit the activation of spermatozoa and how they reduce the fertility of the capacitated spermatozoa (decapacitation). In previous studies it has already been shown that SVS2 acts as a capacitation inhibitor and a decapacitation factor and Araki et al (2016) build up on this pre existent knowledge about SVSs other than SVS2. The investigation utilised CD-1 mice, in particular female mice, to show the effects of SVS3 and SVS4 on sperm cells in the female reproductive tract. <br />
<br />
<br />
Levels of SVS3 and SVS4 were measured in each part of the female reproductive tract such as the copulaatory plug, vagina, oviduct and uterine region near the vagina and oviduct 1.5 hours post copulation. By using anti SVS3 antibody there were clear indications as to the specific roles of SVS3. Results showed that there were no SVS3 proteins in any of the aforementioned parts of the reproductive tract and thus the protein alone had no effects on sperm capacitation. In saying that, SVS3 proteins did show that they had the ability to potentiate the effects of SVS2. Similarly anti SVS4 antibody was utilised to provide insight into the function of this particular protein. Contrary to the findings for SVS3, SVS4 was detected in the uterus but not in any other part of the tract. This suggests that SVS4 has similar activity to that of SVS2 in a way that both the proteins enter the uterus. Thus, SVS4 acts as a capacitation inhibitor similar to SVS2 but results indicated that it does not have the decapacitation effect like SVS2.<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 18 August 2016 - You have added the citation correctly and written a good summary of this very recent article, still only available in the pre-published submitted format, findings. One thing, you must always include the full term in your summary (even if it appears in the paper title) before you begin to use the acronym. "SVS" (seminal vesicle protein secretion) could and may mean different things in different contexts.<br />
<br />
<br />
| width=100px| Assessment 5/5<br />
|}<br />
<br />
==Assessment 2==<br />
<br />
[[File:Development_of_mouse_embryo_in_early_stages.png|400px|thumb|centre|Live imaging of the whole mouse embryo at E6 (A to D) and E5.5. (E to H)<ref><pubmed>23861733</pubmed></ref>]]<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 29 August 2016 - Reference and Copyright correctly included with the file and referenced on your page here. You have not included the <nowiki>{{Student Image}}</nowiki> template in the file summary box.<br />
<br />
| Assessment 4.5/5<br />
|}<br />
<br />
===References===<br />
<br />
<br />
<br />
== Lab 3 Assessment ==<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 31 August 2016 - Lab 3 Assessment Quiz - [[Lecture_-_Mesoderm_Development|Mesoderm]] and [[Lecture_-_Ectoderm_Development|Ectoderm]] development. All correct, Well done!<br />
<br />
| Assessment 5/5<br />
|}<br />
<br />
<br />
==Assessment 4==<br />
==Quiz==<br />
<br />
<quiz display=simple><br />
<br />
{Which of the following structures does the ectoderm contribute to?<br />
|type="()"}<br />
- epithelium, mesentry, connective tissue<br />
+ enteric nervous system<br />
- epithelium and smooth muscle<br />
- enteric nervous system, connective tissue, smooth muscle<br />
|| Option two is correct as the ectoderm only contributes to the enteric nervous system. Epithelium is contributed by the endoderm, whereas the mesentry, connective tissues, smooth muscle, blood vessels are contributed by the mesoderm<br />
<br />
{What lies rostral in relation to the notochord?<br />
|type="()"}<br />
- mesoderm<br />
- the neural tube<br />
+ the buccopharyngeal membrane<br />
- the mesoderm then endoderm<br />
|| The buccopharyngeal membrane lies rostral in relation to the notochord. The mesoderm lies laterally to the notochord, the neural tube dorsally and the mesoderm and endoderm ventrally.<br />
<br />
{During Week 8- 10 (GA 10- 12 weeks):<br />
|type="()"}<br />
+ neural crest migrates into the wall forms enteric nervous system<br />
- endoderm in the GIT wall proliferates<br />
- a second rotation (of 90 degrees) occurs on the longitudinal axis establishing the adult orientation of the stomach.<br />
- mesoderm within the dorsal mesogastrium form a long strip of cells adjacent to the forming stomach above the developing pancreas<br />
|| Option A is correct and is the only one that occurs during weeks 8-10. Option B occurs at the beginning of Week 5. Option C occurs during Week 4. Option D also occurs in Week 5 and is incorrect<br />
<br />
{Narrowing of a lumen such as the duodenum or the pylorus is also called:<br />
|type="()"}<br />
- duplication<br />
- atresia.<br />
+ stenosis<br />
- gastroschisis<br />
|| Stenosis is the correct answer. Duplication is the incomplete recanalization resulting in parallel lumens, this is really a specialized form of stenosis. Atresia is the interuption of the lumen and gastroschisis is a congenital abdominal wall defect which results in herniation of fetal abdominal viscera into the amniotic cavity.<br />
<br />
</quiz><br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 13 October 2016 - These seem good quiz questions. Question 1 should have been worded "Which of the following GIT structures". The other questions and your answers are fine.<br />
<br />
| Assessment 5/5<br />
|}<br />
<br />
[[Student Page]]<br />
<br />
==Lab 6 Assessment==<br />
<br />
Completed ANAT2341 Lab 5 - Course Feedback Questionnaire<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 11 October 2016 - Questionnaire on course structure.<br />
| Assessment 5/5<br />
|}<br />
<br />
==Lab 6 Assessment==<br />
<br />
===Identify a known genetic mutation that is associated with cleft lip or palate===<br />
<br />
Tbx22 mutations are associated with cleft lip/palate<br />
<br />
===Identify a recent research article on this gene===<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/21375406 Arunee Kaewkhampa, D.D.S., M.S., Dhirawat Jotikasthira, D.D.S., M.S., Sutti Malaivijitnond, D.D.S., M.S.,<br />
Piranit Kantaputra, D.D.S., M.S '''TBX22 Mutation Associated With Cleft Lip/Palate, Hypodontia, and Limb Anomaly''' Cleft Palate Craniofacial Journal.: 2012, 49(2); 240-4 PubMed 21375406]<br />
<br />
===How does this mutation affect developmental signalling in normal development===<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 13 October 2016 - This assessment is incomplete.<br />
| Assessment 2/5<br />
|}<br />
<br />
==Lab 7 Assessment==<br />
<br />
===Muscular Dystrophy===<br />
<br />
'''''What is/are the dystrophin mutation(s)?'''''<br />
<br />
The mutations in the dystrophin gene can sequentially lead to two types of muscular dystrophies; Duchene (DMD) and Becker (BMD) muscular dystrophy. DMD is the largest known gene in humans measuring 2.4Mb. The gene provides the coding for the a protein called dystrophin which is located primarily in muscles (skeletal and cardiac) and in minor quantities in nerve cells. In most cases mutations in this gene are of the deletion type in which pieces of DNA are lost. Other types of mutations include large duplications (pieces of DNA are copied) and point mutations (small changes in the DNA code). The aforementioned dystrophies arise from deletions in the dystrophin gene. <br />
<ref name="PMID23961084 "><pubmed>23961084</pubmed></ref><br />
<br />
<br />
'''''What is the function of dystrophin?'''''<br />
<br />
The dystrophin protein provides a structural link between the cytoskeleton of muscles and the extracellular matrix which attributes to maintaining the muscle integrity. It is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Although not much is known about the protein it is thought to cause membrane stabilisation and a lack of the protein can activate multiple pathophysiological processes. <br />
<ref name="PMID11917091"><pubmed>11917091</pubmed></ref><br />
<br />
<br />
'''''What other tissues/organs are affected by this disorder?'''''<br />
<br />
A gradual deterioration in lung function occurs as respiratory muscles weaken resulting in respiratory failure. The heart can also be affected in 1 of 2 ways namely abnormal heart rhythms and cardiomyopathy. <br />
<br />
<br />
<br />
'''''What therapies exist for DMD?'''''<br />
<br />
There is no cure for the disease as of yet but there are various research programs worldwide tackling this issue. There are also measures that can help manage the condition and improve quality of life. These include exercise, supportive environment, medical treatment (steroid treatment mostly), nutrition, surgeries, and palliative care. Other therapies that are currently under going research include gene therapy, reading through stop signals, stem cell therapy, utrophin upregulation, moosting muscle growth and reducing muscle damage<br />
<ref name="PMID22533379"><pubmed>22533379</pubmed></ref> <br />
<br />
<br />
'''''What animal models are available for muscular dystrophy?'''''<br />
<br />
The mouse is used animal model for muscular dystrophy. Other animal that have been utilised include the golden retriever dog and pigs. <br />
<ref name="PMID22137430"><pubmed>22137430</pubmed></ref><br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 13 October 2016 - These are good responses including referencing.<br />
| Assessment 5/5<br />
|}<br />
<br />
=<u>Lab 9 Peer Review</u>=<br />
<br><br />
<font size="4"><u>Group 1:</u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br><br />
Upon initially glancing over the project you can clearly see a range on headings and subheadings and it is evident by these that the project is about the WnT signalling pathway in skin of fetus. This is sufficient for assessment criteria 1 and 2 as you can see the aspect of research they are targeting such as skin formation during embryonic development. Throughout the text you can see citations relating to the topic and a range of references at the end of the project. This satisfies the requirements for criteria 3 but just a small critique would be to put these references in the references section just to clear out the unnecessary area. It can also be commended that the group project goes above and beyond the curriculum of informing us about the background information of WnT signalling pathway in skin of fetus but also includes the complications and diseases arising due to abnormalities in the WnT pathway. This is excellent and satisfies the requirements for criteria 5<br />
<br><br />
<br><br />
There can be some improvements in the project but they are not necessarily of the utmost importance. Firstly, the group can add other specific subheadings and the relevant information under them such as the history or background of the signalling pathway. This is just so the reader has a more rounded knowledge of the pathway and can increase the interest and keep them engaged. It would also be good to see in the text and not just at the end of a paragraph. Such as, in the canonical and non canonical pathway heading it would be recommended to have in text citation and not just at the end just to show the reader where the information was gathered from.<br />
<br><br />
<br><br />
<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Although the project has a fair amount of positives there are some areas that are lacking. Firstly, the report requires additional information in each section and how this information can be linked to pathways in embryological development. It would also be recommended to put in diagrams, images, tables etc. This would engage the reader and make the read more interesting since at the moment there are no images or tables. Also doing so will satisfy one aspect of criteria 2. This way the audience can develop a visual understanding of the topic. It would be advisable to put tables in the history section in the form of relevant dates/years and the information corresponding to the year. <br />
<br><br />
<br><br />
Also, it would be good to see the role of WnT signalling pathway in something other than skin, for eg: an organ or tissue or cell. This would aid in achieving a higher mark for criteria 5 as you go above the required information. Overall it was great to see all group members contributing to the project but minor edits such as citations, images, tables, and adding additional information to sections would really captivate the reader and make it an enjoyable read. <br />
<br><br />
<br><br />
<font size="4"><u>Group 3:</u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements: </b><br />
<br><br />
<br><br />
The group project looks terrific at the initial glance. You can clearly see all the headings and subheadings. In particular, it is great to see a range of subheadings such as “limb bud formation”, “bone development”, “kidney development”. This shows that there was a lot of research put into this project. Also by doing so you have made it clear that your project is about the Fibroblast Growth Factor Receptor Pathway (FGFR). The page is also very easy to navigate as well which was nice to see. <br />
<br><br />
<br><br />
It is also great to see that there is addition of tables, images, and diagrams as it kept the read a lot more interesting and captivating. This allowed you to successfully satisfy criteria 2. It is also good to see correct in text citations and references as this allowed the reader to search for additional information if interested or necessary. Although you haven’t made up any multiple choice questions it is excellent to see a MCQ section. This is a great way to test the readers’ knowledge and in turn you can reflect if you have provided accurate and sufficient information to answer these questions. <br />
<br><br />
<br><br />
It was great to see that you added an abnormalities section and in particular different types of syndromes and disorders. This meant that you went over the minimum information required and put in extra effort to create a coherent project. This satisfied criteria 5 and thus a better project. Overall there are many positives in this report and with minor amendments such as adding information to sections such as “Apert syndrome”, “Animal models”, “Kidney development”, “external genitalia development” etc, a very articulate and well rounded project will be created.<br />
<br><br />
<br><br />
<br />
<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Although there are many positives in the project, there should be some amendments to the project just to ensure all bases are covered. Firstly, it would be advised to increase the amount of information to the introduction and history sections. As these sections are lacking information, the reader may not have enough information to carry on reading as their base on this topic isn’t really strong and lacks information. This can easily turn off new readers and inhibit further exploration of the topic/ project. By adding additional dates in the history section, a better overall knowledge and background of the signalling pathway can be developed which can only enhance learning. <br />
<br><br />
<br><br />
Overall, there are not many negatives and I believe as a reader your project was a great example of progress so far and with the aforementioned minor tweaks, your group is well on their way to achieving extremely high marks. <br />
<br><br />
<br><br />
<font size="4"><u>Group 4:</u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
At initial glance I can see a range of headings and subheadings which just made it easier to navigate from one aspect of the project to another. This satisfied the requirements for criteria 1 and 2. This also allowed me to recognise the main topic of the project is the Hedgehog signalling pathway. There is also an addition of an image of the pathway which was great to see as it outlines the main components of the pathway and in general educates the reader about the signalling pathway. This provided a visual stimulus/ description which in turn engaged the reader to find out more about the topic.<br />
<br><br />
<br><br />
It was also good to see correct in text citations and a references list at the end which in turn satisfied criteria 3. To satisfy criteria 5 it was excellent to see information that was well beyond the required information. An example of this is when discussing the role of the pathway in not only humans but also in mice, chicks and fruit flies. The group also began to include new research and abnormalities related to the Shh pathway which aided in rounding off criteria 1. <br />
<br><br />
<br><br />
In order to improve the already positives of this project it would be advised to add a description to the image just so the reader can have some sort of summary about the main points of the image/ pathway. Also, addition of diagrams or tables in some of the subheadings would be good as it will keep the reader interested and in general provide a visual aid. Also it is necessary to cite and provide a reference of the image as it breaches the copyright laws. <br />
<br><br />
<br><br />
<b>Negative aspects of the project and suggested improvements: </b><br />
<br><br />
<br><br />
Although there are positives to the project, there are a few negatives that can easily be fixed. It is crucial to put in an “Introduction” heading and providing relevant information. This in turn will create a coherent project as it flows from one aspect to another whilst simultaneously providing a brief overview of the Sonic Hedgehog Pathway. Although you have explored the mechanism in animal models it is imperative to link this to embryological development. Also, addition of diagrams, interactive quizzes and tables is necessary to satisfy criteria 3, since 1 image is not enough. <br />
<br><br />
<br><br />
Adding a glossary of terms at the end of the project is needed to clarify any words or phrases that have not been previously encountered such as “organogenesis”, “paracrine”, “dephosphorylation” etc. Overall, the project is coming along nicely and with the recommended amendments, a high mark is definitely in order. <br />
<br><br />
<br><br />
<font size="4"><u>Group 5: </u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Upon reviewing the page, it is evident that there has been a lot of research put in this project. Initially, there is evidence of a range of headings and subheadings which allowed the navigation from one aspect of the project to another extremely easy. This allowed me to confirm that the project is about T-box genes and their signalling. Secondly, it was excellent to see a range of images, tables and graphs as they provided visual aids to learn more about the topic and in general made it easier to accumulate information. Also it was good to see that these tables and images were correctly cited and referenced at the end which meant that there was no breach of copyright laws. <br />
<br><br />
<br><br />
Also, throughout the project there was sufficient amount of information in each subheading which meant that the reader gained all relevant information pertaining to the section that they are reading. It was also great to see a range of abnormalities being added to the project. This meant that you have went above and beyond the scope of the assessment and researched that extra bit to provide additional information about the signalling pathway and complications arising from any mutations. This meant that you successfully satisfied criteria 5 and thus a more rounded project. <br />
<br><br />
<br><br />
<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
This project certainly contains a range of positives but there were minimal negatives that can easily be amended in order to achieve a very high mark. I noticed that there was more than 1 image being used from Wikipedia and the criterion clearly says that a maximum of 1 was allowed. This is not a big deal but just in case there is harsh marking and penalties, it is advised to replace the additional image with another image. In addition, it would be useful to add a glossary of all the terms that one may find confusing such as “homologues”, “heterozygous”, “homology”, “notochord” etc. This in turn will provide the reader with enough information to understand the context of the project and in turn keep them engaged.<br />
<br><br />
<br><br />
Another negative aspect of the project was that the subheading “Ancient origins and evolution of the T-box gene family” randomly appearing nearing the end of the project. This looked a bit out of place and not flowing with the rest of the passage. To correct this it would be advised to add this to the start of the page with the “Origin of the T-box genes” section just so the information clearly flows from one topic to another without creating confusion. Overall, this project is coming along quite nicely. It is evident that a lot of research has been put into constructing a coherent and succinct project but also have the visual cues to back up the main aspects. To maximise marks, it is recommended to reflect on the feedback and correct the minor mistakes. <br />
<br><br />
<br><br />
<font size="4"><u>Group 6:</u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Upon reviewing the page I can see a number of headings and subheadings such as the nature of the growth factor, its mechanism of action, history and emerging research. But to be critical, a range of other headings is necessary to ensure all bases are covered when researching and providing the relevant information. This will help in satisfying the requirements for criteria 1 and 2. It is good to see the addition of a diagram to your project as it is a requirement for criteria 2. This provided a visual aid that kept me interested to find out more about the topic while simultaneously making it easier to understand the theory behind the process of TGF Beta signalling pathway. It is also great to see the current research and limitations as this shows that you are going beyond the scope of the required criteria and researching ahead to provide that extra bit of information. This in turn is a great way to satisfy criteria 5.<br />
<br><br />
<br><br />
<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Although there are a few positives in the project, there are a number of negatives which can be improved upon to ensure a coherent project is created. Firstly, it is advised to put the heading “history of TGF- beta signalling pathway at the top” with the introduction as this is an introductory section and should be addressed initially on the page. This will allow you to create a more flowing page which also looks nice. Secondly, it would be advised to add more images and tables as it is a requirement for criteria 2. By doing this you will keep the reader engaged and wanting to find out more about the chosen topic. In saying that, you already have a couple of images but not referenced. It is imperative to correctly cite and reference these images as failure to do so will result in a breach of copyright laws. <br />
<br><br />
<br><br />
Another critique is to add more subheadings with a range of different aspects of the signalling pathway being explored. It is recommended that you dedicate a chunk of your project to describing the pathway in detail and its role in embryonic development and abnormalities relating to mutations caused by the pathway. This will ensure you answer criteria 6 as it is a great deal of the report. It is also advised to put the history section under the introduction section as placing it in the middle of the project is a bit out of place and inhibits the flow of the information from one subheading to another. Also, the history section can be improved by adding more information as there have been more findings in this research topic since the 1970s. An addition of glossary is also needed for terms such as “peptide”, “cytokine”, “angiogenesis”, “protein kinase” etc. This will aid readers understand terms that they previously have not encountered and allow them to correctly understand the context of the information. <br />
<br><br />
<br><br />
It has also come to my attention that there are little to no references or in text citations. By adding information without correctly giving the authors credit is a breach of copyright laws and must be done urgently. Overall, the project shows signs of progress with a number of positives. By reflecting on the negative aspects and acting upon it, it is certain that high marks are in order.<br />
<br />
<br />
{{Stem Cell Presentations 2016}}<br />
<br />
===Lab 11 Assessment===<br />
<br />
Ischemic myocardial infarction causes irreversible cell loss and scarring and is a major source of morbidity and mortality in humans. Thus, the inability to replace damaged cardiac muscle ranks among the most prominent regenerative failures of mammals. The investigation by Lepilina et al studied Zebrafish, an animal with a unique yet poorly understood capacity for cardiac regeneration. Their results indicated that the regeneration of the myocardium occurs through 2 coordinated stages after the resection of the ventricular apex. Initially, a blastema is formed, a mass of cells capable of growth and regeneration into organs or body parts. They are comprised of progenitor cells that express precardiac markers and undergo differentiation and proliferation. In the second stage, the tissue surrounding both cardiac chambers induces developmental markers and exponentially expands. This creates a new epithelium cover for the underlying exposed myocardium. New vasculature then forms supplying the regeneration muscle by epicardial cells invading the wound. These cells undergo epithelial-to-mesenchymal transition (EMT). The fibroblast growth factor of subtype 17 b (fgf17b) in induced in the myocardium in the regenerative phase whereas the receptors fgfr2 and fgfr4 are induced in neighbouring epicardial derived cells. The investigation revealed that injury to the myocardium or the epicardial tissue collaborate in an Fgf-dependent manner to achieve cardiac regeneration.<br />
<br />
This primary article is related to the review article in several ways. Since adult myocardium is prone to scarring and hypertrophy leading to fatal arrythmias and heart failure, cardiac regeneration in mammals (especially humans) shows low proliferative capacity. This is juxtaposed in the review article by relating it to the mechanisms in the zebrafish, which shows that they can in fact regenerate cardiac muscle after injury, suggesting that latent regenerative potential exists. The review article also draws differences in the inability of mammals to regenerate crucial structures, including limbs, spinal cord and cardiac muscle. However, zebrafish etain the ability to regenerate these and other organs. Thus there is some significance as to how such animals have these fundamental aspects in relation to cardiac regeneration and their ability to repair themselves efficiently. Thus the primary research article provides an understanding of the processes and mechanisms that help certain species to allow proliferation of cardiomyocytes which can aid in generating new targets for therapeutic manipulation.</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z5014803&diff=255394
User:Z5014803
2016-10-27T13:57:48Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Student2016}}<br />
<br />
==Lab Attendance==<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 18:29, 5 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:40, 12 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:07, 19 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:09, 26 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:45, 2 September 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:13, 9 September 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:46, 23 September 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:58, 7 October 2016 (AEDT)<br />
<br />
<br />
===Belbin Team Roles===<br />
In my previous courses, I was introduced to the Bebin model team roles as a way to identify myself in a team scenario. I definitely see myself as a "Shaper" since I am driven to try and complete the task at hand as soon as possible to ensure sufficient time for the editing process and the refining of the task. I also agree that I motivate other team members to progress through the task at a efficient pace such that the group does not lose momentum. I am also a person who is not afraid to speak my mind and thus will contest other viewpoints in order to spark a discussion. I identify myself as a very dynamic person in the way that I act according to the different predicaments I'm in and this results in numerous ways of efficiently solving any problems. Although I identify myself as a Shape I do not agree that i can become aggressive or bad humoured as I see some traits of a Co-ordinator in me. I have a very mature approach and recognise that each individual has a different way of attacking a problem and have learnt to appreciate others. <br />
<br />
===Lecture 1: Fertilisation===<br />
I have always been fond of the details surrounding fertilisation as it seems like a very interesting topic. It is more than just a sperm and egg cell coming together. The first lecture on fertilisation highlighted the various processes that need to occur in order to form a zygote, from gametogenesis to fertilisation and then forming the zygote. In my first year studies I learnt that there is a mechanism to prevent multiple sperm cells to enter the ovum but wasnt familiar with the process. The most interesting aspect of this lecture was precisely the process from fertilisation to the prevention of polyspermy. I was intrigued by how sperm cells are attracted to the oocyte which was through the ZP2 protein and only the nucleus of the spermatozoa enters the cell membranes. I was also interested in how membrane fusion will result in oocyte processes that will prevent polyspermy through the elevation of intracellular calcium levels. I had minimal knowledge of this topic but the lecture really made me want to learn about this process in a lot more detail.<br />
<br />
==New SubHeading==<br />
===External Link===<br />
[http://www.smh.com.au/ SMH]<br />
<br />
===Internal Link===<br />
[[ANAT2341 Lab 1]]<br />
<br />
[[ANAT2341 Lab 1|Fertilization Lab]]<br />
<br />
[[Student Page]]<br />
<br />
==Referencing==<br />
[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=fertilization fertilization]<br />
<br />
PMID 27486480<br />
<br />
==Assessment 1==<br />
<br />
<pubmed>27486266</pubmed> <br />
<br />
In order for fertilization to occur spermatozoa must be activated in a process known as 'sperm capacitation'. The primary research article "Seminal vesicle proteins SVS3 and SVS4 facilitate SVS2 effect on sperm capacitation" by Araki et al (2016) investigate the role of seminal vesicle secretion and how they inhibit the activation of spermatozoa and how they reduce the fertility of the capacitated spermatozoa (decapacitation). In previous studies it has already been shown that SVS2 acts as a capacitation inhibitor and a decapacitation factor and Araki et al (2016) build up on this pre existent knowledge about SVSs other than SVS2. The investigation utilised CD-1 mice, in particular female mice, to show the effects of SVS3 and SVS4 on sperm cells in the female reproductive tract. <br />
<br />
<br />
Levels of SVS3 and SVS4 were measured in each part of the female reproductive tract such as the copulaatory plug, vagina, oviduct and uterine region near the vagina and oviduct 1.5 hours post copulation. By using anti SVS3 antibody there were clear indications as to the specific roles of SVS3. Results showed that there were no SVS3 proteins in any of the aforementioned parts of the reproductive tract and thus the protein alone had no effects on sperm capacitation. In saying that, SVS3 proteins did show that they had the ability to potentiate the effects of SVS2. Similarly anti SVS4 antibody was utilised to provide insight into the function of this particular protein. Contrary to the findings for SVS3, SVS4 was detected in the uterus but not in any other part of the tract. This suggests that SVS4 has similar activity to that of SVS2 in a way that both the proteins enter the uterus. Thus, SVS4 acts as a capacitation inhibitor similar to SVS2 but results indicated that it does not have the decapacitation effect like SVS2.<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 18 August 2016 - You have added the citation correctly and written a good summary of this very recent article, still only available in the pre-published submitted format, findings. One thing, you must always include the full term in your summary (even if it appears in the paper title) before you begin to use the acronym. "SVS" (seminal vesicle protein secretion) could and may mean different things in different contexts.<br />
<br />
<br />
| width=100px| Assessment 5/5<br />
|}<br />
<br />
==Assessment 2==<br />
<br />
[[File:Development_of_mouse_embryo_in_early_stages.png|400px|thumb|centre|Live imaging of the whole mouse embryo at E6 (A to D) and E5.5. (E to H)<ref><pubmed>23861733</pubmed></ref>]]<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 29 August 2016 - Reference and Copyright correctly included with the file and referenced on your page here. You have not included the <nowiki>{{Student Image}}</nowiki> template in the file summary box.<br />
<br />
| Assessment 4.5/5<br />
|}<br />
<br />
===References===<br />
<br />
<br />
<br />
== Lab 3 Assessment ==<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 31 August 2016 - Lab 3 Assessment Quiz - [[Lecture_-_Mesoderm_Development|Mesoderm]] and [[Lecture_-_Ectoderm_Development|Ectoderm]] development. All correct, Well done!<br />
<br />
| Assessment 5/5<br />
|}<br />
<br />
<br />
==Assessment 4==<br />
==Quiz==<br />
<br />
<quiz display=simple><br />
<br />
{Which of the following structures does the ectoderm contribute to?<br />
|type="()"}<br />
- epithelium, mesentry, connective tissue<br />
+ enteric nervous system<br />
- epithelium and smooth muscle<br />
- enteric nervous system, connective tissue, smooth muscle<br />
|| Option two is correct as the ectoderm only contributes to the enteric nervous system. Epithelium is contributed by the endoderm, whereas the mesentry, connective tissues, smooth muscle, blood vessels are contributed by the mesoderm<br />
<br />
{What lies rostral in relation to the notochord?<br />
|type="()"}<br />
- mesoderm<br />
- the neural tube<br />
+ the buccopharyngeal membrane<br />
- the mesoderm then endoderm<br />
|| The buccopharyngeal membrane lies rostral in relation to the notochord. The mesoderm lies laterally to the notochord, the neural tube dorsally and the mesoderm and endoderm ventrally.<br />
<br />
{During Week 8- 10 (GA 10- 12 weeks):<br />
|type="()"}<br />
+ neural crest migrates into the wall forms enteric nervous system<br />
- endoderm in the GIT wall proliferates<br />
- a second rotation (of 90 degrees) occurs on the longitudinal axis establishing the adult orientation of the stomach.<br />
- mesoderm within the dorsal mesogastrium form a long strip of cells adjacent to the forming stomach above the developing pancreas<br />
|| Option A is correct and is the only one that occurs during weeks 8-10. Option B occurs at the beginning of Week 5. Option C occurs during Week 4. Option D also occurs in Week 5 and is incorrect<br />
<br />
{Narrowing of a lumen such as the duodenum or the pylorus is also called:<br />
|type="()"}<br />
- duplication<br />
- atresia.<br />
+ stenosis<br />
- gastroschisis<br />
|| Stenosis is the correct answer. Duplication is the incomplete recanalization resulting in parallel lumens, this is really a specialized form of stenosis. Atresia is the interuption of the lumen and gastroschisis is a congenital abdominal wall defect which results in herniation of fetal abdominal viscera into the amniotic cavity.<br />
<br />
</quiz><br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 13 October 2016 - These seem good quiz questions. Question 1 should have been worded "Which of the following GIT structures". The other questions and your answers are fine.<br />
<br />
| Assessment 5/5<br />
|}<br />
<br />
[[Student Page]]<br />
<br />
==Lab 6 Assessment==<br />
<br />
Completed ANAT2341 Lab 5 - Course Feedback Questionnaire<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 11 October 2016 - Questionnaire on course structure.<br />
| Assessment 5/5<br />
|}<br />
<br />
==Lab 6 Assessment==<br />
<br />
===Identify a known genetic mutation that is associated with cleft lip or palate===<br />
<br />
Tbx22 mutations are associated with cleft lip/palate<br />
<br />
===Identify a recent research article on this gene===<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/21375406 Arunee Kaewkhampa, D.D.S., M.S., Dhirawat Jotikasthira, D.D.S., M.S., Sutti Malaivijitnond, D.D.S., M.S.,<br />
Piranit Kantaputra, D.D.S., M.S '''TBX22 Mutation Associated With Cleft Lip/Palate, Hypodontia, and Limb Anomaly''' Cleft Palate Craniofacial Journal.: 2012, 49(2); 240-4 PubMed 21375406]<br />
<br />
===How does this mutation affect developmental signalling in normal development===<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 13 October 2016 - This assessment is incomplete.<br />
| Assessment 2/5<br />
|}<br />
<br />
==Lab 7 Assessment==<br />
<br />
===Muscular Dystrophy===<br />
<br />
'''''What is/are the dystrophin mutation(s)?'''''<br />
<br />
The mutations in the dystrophin gene can sequentially lead to two types of muscular dystrophies; Duchene (DMD) and Becker (BMD) muscular dystrophy. DMD is the largest known gene in humans measuring 2.4Mb. The gene provides the coding for the a protein called dystrophin which is located primarily in muscles (skeletal and cardiac) and in minor quantities in nerve cells. In most cases mutations in this gene are of the deletion type in which pieces of DNA are lost. Other types of mutations include large duplications (pieces of DNA are copied) and point mutations (small changes in the DNA code). The aforementioned dystrophies arise from deletions in the dystrophin gene. <br />
<ref name="PMID23961084 "><pubmed>23961084</pubmed></ref><br />
<br />
<br />
'''''What is the function of dystrophin?'''''<br />
<br />
The dystrophin protein provides a structural link between the cytoskeleton of muscles and the extracellular matrix which attributes to maintaining the muscle integrity. It is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Although not much is known about the protein it is thought to cause membrane stabilisation and a lack of the protein can activate multiple pathophysiological processes. <br />
<ref name="PMID11917091"><pubmed>11917091</pubmed></ref><br />
<br />
<br />
'''''What other tissues/organs are affected by this disorder?'''''<br />
<br />
A gradual deterioration in lung function occurs as respiratory muscles weaken resulting in respiratory failure. The heart can also be affected in 1 of 2 ways namely abnormal heart rhythms and cardiomyopathy. <br />
<br />
<br />
<br />
'''''What therapies exist for DMD?'''''<br />
<br />
There is no cure for the disease as of yet but there are various research programs worldwide tackling this issue. There are also measures that can help manage the condition and improve quality of life. These include exercise, supportive environment, medical treatment (steroid treatment mostly), nutrition, surgeries, and palliative care. Other therapies that are currently under going research include gene therapy, reading through stop signals, stem cell therapy, utrophin upregulation, moosting muscle growth and reducing muscle damage<br />
<ref name="PMID22533379"><pubmed>22533379</pubmed></ref> <br />
<br />
<br />
'''''What animal models are available for muscular dystrophy?'''''<br />
<br />
The mouse is used animal model for muscular dystrophy. Other animal that have been utilised include the golden retriever dog and pigs. <br />
<ref name="PMID22137430"><pubmed>22137430</pubmed></ref><br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 13 October 2016 - These are good responses including referencing.<br />
| Assessment 5/5<br />
|}<br />
<br />
=<u>Lab 9 Peer Review</u>=<br />
<br><br />
<font size="4"><u>Group 1:</u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br><br />
Upon initially glancing over the project you can clearly see a range on headings and subheadings and it is evident by these that the project is about the WnT signalling pathway in skin of fetus. This is sufficient for assessment criteria 1 and 2 as you can see the aspect of research they are targeting such as skin formation during embryonic development. Throughout the text you can see citations relating to the topic and a range of references at the end of the project. This satisfies the requirements for criteria 3 but just a small critique would be to put these references in the references section just to clear out the unnecessary area. It can also be commended that the group project goes above and beyond the curriculum of informing us about the background information of WnT signalling pathway in skin of fetus but also includes the complications and diseases arising due to abnormalities in the WnT pathway. This is excellent and satisfies the requirements for criteria 5<br />
<br><br />
<br><br />
There can be some improvements in the project but they are not necessarily of the utmost importance. Firstly, the group can add other specific subheadings and the relevant information under them such as the history or background of the signalling pathway. This is just so the reader has a more rounded knowledge of the pathway and can increase the interest and keep them engaged. It would also be good to see in the text and not just at the end of a paragraph. Such as, in the canonical and non canonical pathway heading it would be recommended to have in text citation and not just at the end just to show the reader where the information was gathered from.<br />
<br><br />
<br><br />
<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Although the project has a fair amount of positives there are some areas that are lacking. Firstly, the report requires additional information in each section and how this information can be linked to pathways in embryological development. It would also be recommended to put in diagrams, images, tables etc. This would engage the reader and make the read more interesting since at the moment there are no images or tables. Also doing so will satisfy one aspect of criteria 2. This way the audience can develop a visual understanding of the topic. It would be advisable to put tables in the history section in the form of relevant dates/years and the information corresponding to the year. <br />
<br><br />
<br><br />
Also, it would be good to see the role of WnT signalling pathway in something other than skin, for eg: an organ or tissue or cell. This would aid in achieving a higher mark for criteria 5 as you go above the required information. Overall it was great to see all group members contributing to the project but minor edits such as citations, images, tables, and adding additional information to sections would really captivate the reader and make it an enjoyable read. <br />
<br><br />
<br><br />
<font size="4"><u>Group 3:</u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements: </b><br />
<br><br />
<br><br />
The group project looks terrific at the initial glance. You can clearly see all the headings and subheadings. In particular, it is great to see a range of subheadings such as “limb bud formation”, “bone development”, “kidney development”. This shows that there was a lot of research put into this project. Also by doing so you have made it clear that your project is about the Fibroblast Growth Factor Receptor Pathway (FGFR). The page is also very easy to navigate as well which was nice to see. <br />
<br><br />
<br><br />
It is also great to see that there is addition of tables, images, and diagrams as it kept the read a lot more interesting and captivating. This allowed you to successfully satisfy criteria 2. It is also good to see correct in text citations and references as this allowed the reader to search for additional information if interested or necessary. Although you haven’t made up any multiple choice questions it is excellent to see a MCQ section. This is a great way to test the readers’ knowledge and in turn you can reflect if you have provided accurate and sufficient information to answer these questions. <br />
<br><br />
<br><br />
It was great to see that you added an abnormalities section and in particular different types of syndromes and disorders. This meant that you went over the minimum information required and put in extra effort to create a coherent project. This satisfied criteria 5 and thus a better project. Overall there are many positives in this report and with minor amendments such as adding information to sections such as “Apert syndrome”, “Animal models”, “Kidney development”, “external genitalia development” etc, a very articulate and well rounded project will be created.<br />
<br><br />
<br><br />
<br />
<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Although there are many positives in the project, there should be some amendments to the project just to ensure all bases are covered. Firstly, it would be advised to increase the amount of information to the introduction and history sections. As these sections are lacking information, the reader may not have enough information to carry on reading as their base on this topic isn’t really strong and lacks information. This can easily turn off new readers and inhibit further exploration of the topic/ project. By adding additional dates in the history section, a better overall knowledge and background of the signalling pathway can be developed which can only enhance learning. <br />
<br><br />
<br><br />
Overall, there are not many negatives and I believe as a reader your project was a great example of progress so far and with the aforementioned minor tweaks, your group is well on their way to achieving extremely high marks. <br />
<br><br />
<br><br />
<font size="4"><u>Group 4:</u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
At initial glance I can see a range of headings and subheadings which just made it easier to navigate from one aspect of the project to another. This satisfied the requirements for criteria 1 and 2. This also allowed me to recognise the main topic of the project is the Hedgehog signalling pathway. There is also an addition of an image of the pathway which was great to see as it outlines the main components of the pathway and in general educates the reader about the signalling pathway. This provided a visual stimulus/ description which in turn engaged the reader to find out more about the topic.<br />
<br><br />
<br><br />
It was also good to see correct in text citations and a references list at the end which in turn satisfied criteria 3. To satisfy criteria 5 it was excellent to see information that was well beyond the required information. An example of this is when discussing the role of the pathway in not only humans but also in mice, chicks and fruit flies. The group also began to include new research and abnormalities related to the Shh pathway which aided in rounding off criteria 1. <br />
<br><br />
<br><br />
In order to improve the already positives of this project it would be advised to add a description to the image just so the reader can have some sort of summary about the main points of the image/ pathway. Also, addition of diagrams or tables in some of the subheadings would be good as it will keep the reader interested and in general provide a visual aid. Also it is necessary to cite and provide a reference of the image as it breaches the copyright laws. <br />
<br><br />
<br><br />
<b>Negative aspects of the project and suggested improvements: </b><br />
<br><br />
<br><br />
Although there are positives to the project, there are a few negatives that can easily be fixed. It is crucial to put in an “Introduction” heading and providing relevant information. This in turn will create a coherent project as it flows from one aspect to another whilst simultaneously providing a brief overview of the Sonic Hedgehog Pathway. Although you have explored the mechanism in animal models it is imperative to link this to embryological development. Also, addition of diagrams, interactive quizzes and tables is necessary to satisfy criteria 3, since 1 image is not enough. <br />
<br><br />
<br><br />
Adding a glossary of terms at the end of the project is needed to clarify any words or phrases that have not been previously encountered such as “organogenesis”, “paracrine”, “dephosphorylation” etc. Overall, the project is coming along nicely and with the recommended amendments, a high mark is definitely in order. <br />
<br><br />
<br><br />
<font size="4"><u>Group 5: </u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Upon reviewing the page, it is evident that there has been a lot of research put in this project. Initially, there is evidence of a range of headings and subheadings which allowed the navigation from one aspect of the project to another extremely easy. This allowed me to confirm that the project is about T-box genes and their signalling. Secondly, it was excellent to see a range of images, tables and graphs as they provided visual aids to learn more about the topic and in general made it easier to accumulate information. Also it was good to see that these tables and images were correctly cited and referenced at the end which meant that there was no breach of copyright laws. <br />
<br><br />
<br><br />
Also, throughout the project there was sufficient amount of information in each subheading which meant that the reader gained all relevant information pertaining to the section that they are reading. It was also great to see a range of abnormalities being added to the project. This meant that you have went above and beyond the scope of the assessment and researched that extra bit to provide additional information about the signalling pathway and complications arising from any mutations. This meant that you successfully satisfied criteria 5 and thus a more rounded project. <br />
<br><br />
<br><br />
<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
This project certainly contains a range of positives but there were minimal negatives that can easily be amended in order to achieve a very high mark. I noticed that there was more than 1 image being used from Wikipedia and the criterion clearly says that a maximum of 1 was allowed. This is not a big deal but just in case there is harsh marking and penalties, it is advised to replace the additional image with another image. In addition, it would be useful to add a glossary of all the terms that one may find confusing such as “homologues”, “heterozygous”, “homology”, “notochord” etc. This in turn will provide the reader with enough information to understand the context of the project and in turn keep them engaged.<br />
<br><br />
<br><br />
Another negative aspect of the project was that the subheading “Ancient origins and evolution of the T-box gene family” randomly appearing nearing the end of the project. This looked a bit out of place and not flowing with the rest of the passage. To correct this it would be advised to add this to the start of the page with the “Origin of the T-box genes” section just so the information clearly flows from one topic to another without creating confusion. Overall, this project is coming along quite nicely. It is evident that a lot of research has been put into constructing a coherent and succinct project but also have the visual cues to back up the main aspects. To maximise marks, it is recommended to reflect on the feedback and correct the minor mistakes. <br />
<br><br />
<br><br />
<font size="4"><u>Group 6:</u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Upon reviewing the page I can see a number of headings and subheadings such as the nature of the growth factor, its mechanism of action, history and emerging research. But to be critical, a range of other headings is necessary to ensure all bases are covered when researching and providing the relevant information. This will help in satisfying the requirements for criteria 1 and 2. It is good to see the addition of a diagram to your project as it is a requirement for criteria 2. This provided a visual aid that kept me interested to find out more about the topic while simultaneously making it easier to understand the theory behind the process of TGF Beta signalling pathway. It is also great to see the current research and limitations as this shows that you are going beyond the scope of the required criteria and researching ahead to provide that extra bit of information. This in turn is a great way to satisfy criteria 5.<br />
<br><br />
<br><br />
<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Although there are a few positives in the project, there are a number of negatives which can be improved upon to ensure a coherent project is created. Firstly, it is advised to put the heading “history of TGF- beta signalling pathway at the top” with the introduction as this is an introductory section and should be addressed initially on the page. This will allow you to create a more flowing page which also looks nice. Secondly, it would be advised to add more images and tables as it is a requirement for criteria 2. By doing this you will keep the reader engaged and wanting to find out more about the chosen topic. In saying that, you already have a couple of images but not referenced. It is imperative to correctly cite and reference these images as failure to do so will result in a breach of copyright laws. <br />
<br><br />
<br><br />
Another critique is to add more subheadings with a range of different aspects of the signalling pathway being explored. It is recommended that you dedicate a chunk of your project to describing the pathway in detail and its role in embryonic development and abnormalities relating to mutations caused by the pathway. This will ensure you answer criteria 6 as it is a great deal of the report. It is also advised to put the history section under the introduction section as placing it in the middle of the project is a bit out of place and inhibits the flow of the information from one subheading to another. Also, the history section can be improved by adding more information as there have been more findings in this research topic since the 1970s. An addition of glossary is also needed for terms such as “peptide”, “cytokine”, “angiogenesis”, “protein kinase” etc. This will aid readers understand terms that they previously have not encountered and allow them to correctly understand the context of the information. <br />
<br><br />
<br><br />
It has also come to my attention that there are little to no references or in text citations. By adding information without correctly giving the authors credit is a breach of copyright laws and must be done urgently. Overall, the project shows signs of progress with a number of positives. By reflecting on the negative aspects and acting upon it, it is certain that high marks are in order.<br />
<br />
<br />
{{Stem Cell Presentations 2016}}<br />
<br />
==Lab 11 Assessment==<br />
<br />
Ischemic myocardial infarction causes irreversible cell loss and scarring and is a major source of morbidity and mortality in humans. Thus, the inability to replace damaged cardiac muscle ranks among the most prominent regenerative failures of mammals. The investigation by Lepilina et al studied Zebrafish, an animal with a unique yet poorly understood capacity for cardiac regeneration. Their results indicated that the regeneration of the myocardium occurs through 2 coordinated stages after the resection of the ventricular apex. Initially, a blastema is formed, a mass of cells capable of growth and regeneration into organs or body parts. They are comprised of progenitor cells that express precardiac markers and undergo differentiation and proliferation. In the second stage, the tissue surrounding both cardiac chambers induces developmental markers and exponentially expands. This creates a new epithelium cover for the underlying exposed myocardium. New vasculature then forms supplying the regeneration muscle by epicardial cells invading the wound. These cells undergo epithelial-to-mesenchymal transition (EMT). The fibroblast growth factor of subtype 17 b (fgf17b) in induced in the myocardium in the regenerative phase whereas the receptors fgfr2 and fgfr4 are induced in neighbouring epicardial derived cells. The investigation revealed that injury to the myocardium or the epicardial tissue collaborate in an Fgf-dependent manner to achieve cardiac regeneration.<br />
<br />
This primary article is related to the review article in several ways. Since adult myocardium is prone to scarring and hypertrophy leading to fatal arrythmias and heart failure, cardiac regeneration in mammals (especially humans) shows low proliferative capacity. This is juxtaposed in the review article by relating it to the mechanisms in the zebrafish, which shows that they can in fact regenerate cardiac muscle after injury, suggesting that latent regenerative potential exists. The review article also draws differences in the inability of mammals to regenerate crucial structures, including limbs, spinal cord and cardiac muscle. However, zebrafish etain the ability to regenerate these and other organs. Thus there is some significance as to how such animals have these fundamental aspects in relation to cardiac regeneration and their ability to repair themselves efficiently. Thus the primary research article provides an understanding of the processes and mechanisms that help certain species to allow proliferation of cardiomyocytes which can aid in generating new targets for therapeutic manipulation.</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=2016_Group_Project_2&diff=255188
2016 Group Project 2
2016-10-27T08:42:24Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016header}}<br />
{{Group Assessment Criteria table}}<br />
<!-- Do not delete the above template from the Group project page. --><br />
=The Notch Signalling Pathway=<br />
===Introduction===<br />
The Notch signalling pathway is the most prevalent form of intracellular communication in multicellular organisms. It is a critical pathway for cell differentiation, proliferation, and apoptosis. It is involved in embryonic organ development through the regulation of cell-cell signalling; specifically lateral inhibition, formation of boundaries, and cell lineage assignation.<ref name="The Developing Human">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2015). The developing human: clinically oriented embryology (10th ed.). Philadelphia: Saunders.</ref><ref name="PMID10075488">As reviewed by <pubmed>10075488</pubmed></ref> This pathway is also actively involved in adjacent cell communication, developmental process such as adult homeostasis, and stem cell maintenance. Since this pathway is an intricate and crucial aspect of an organism's development and cell signalling, a mutation in the functional components of this pathway can cause a myriad of diseases such as congenital disorders, cancers, strokes, Alagille syndrome, and leukoencephalopathy.<ref name="PMID19255248">As reviewed by <pubmed>19255248</pubmed></ref> The process of Notch signalling primarily utilises a ligand-receptor interaction to release protein fragments at the cellular membrane, which then provide signals to the internal environment of the cell and to adjacent cells. In mammals, the Notch signalling pathway is comprised of four receptors (Notch 1-4) which interact with Delta or Jagged ligands to bring about the activation of this pathway. Homologous Notch genes have been identified in other animals, such as ''Drosophila melanogaster'' (fruit fly) and ''Danio rerio'' (zebrafish).<br />
<br><br />
<br />
<big>What will you find on this wiki page?</big><br />
<br />
This page is designed to provide an overview of such features of the Notch signalling pathway, but is in no way a complete resource for all Notch-related information (especially since this signalling pathway has such a wide array of activities in many organisms and the scientific understanding of it is continuously updating!). By reading this page you should come to a better understanding of Notch in regards to: general molecular mechanisms; embryonic development by systems; examples of animal development; abnormalities and disease; current and potential future research; as well as a couple of links to interesting articles for those who want to read more. There is a [[#Glossary| Glossary]] at the bottom of the page for better understanding of scientific terms used throughout this page, and readers are encouraged to 'expand' any collapsed information on the page to optimise their experience in reading about Notch. <br />
<br><br><br />
<div align="center"><html5media width="560" height="315">https://www.youtube.com/embed/axkDX0XZyN0</html5media></div><br />
<br><br />
<br />
===History===<br />
{| class="pretty table"<br />
|-bgcolor="FAF5FF" <br />
| 1914<br />
| First description of a "notch" defect (loss of tissue in the wing) in ''Drosophila'' by John S. Dexter, giving the gene its name<ref>Dexter, J. (1914). The Analysis of a Case of Continuous Variation in Drosophila by a Study of Its Linkage Relations. ''The American Naturalist'', 48(576), 712-758. Retrieved from http://www.jstor.org/stable/2455888</ref><br />
|-<br />
| 1917<br />
| First allele of ''Notch'' is identified by Thomas Hunt Morgan<ref>Morgan, T. H. (1917). The theory of the gene. ''The American Naturalist'', 51(609), 513-544.</ref><br />
|-bgcolor="FAF5FF" <br />
|-<br />
| 1930s<br />
| Donald F. Poulson conducts research into the involvement of ''Notch'' in development.<ref><pubmed>16588136</pubmed></ref> <br />
|-<br />
| 1958<br />
| An investigation by W.J. Welshons confirmed that the locus of Notch is contained within the 3C7 band of the X chromosome.<ref><pubmed>13635554</pubmed></ref><br />
|-bgcolor="FAF5FF" <br />
|-<br />
| 1983<br />
| DNA sequences belonging to the Notch locus cloned and determined that RNA is required for the function of the wild type Notch. Further insight developed into the function of Notch and its role in differentiation and regeneration.<ref><pubmed>6403942</pubmed></ref><br />
|-<br />
| 1986<br />
| The molecular analysis and sequence of the Notch locus was determined by Michael W. Young and his team. A relationship was identified between the protein encoded by the major Notch transcript and mammalian clotting and growth factors.<ref><pubmed>3097517</pubmed></ref><br />
|-bgcolor="FAF5FF" <br />
|-<br />
| 1989<br />
| Neurogenic loci "Delta" and "Mastermind" identified and research conducted to search for genes which may have an interaction with the Notch protein. It was confirmed that mutations in these loci will affect neurogenesis.<ref><pubmed>2338245</pubmed></ref><br />
|-<br />
| 2012<br />
| The Notch ligand Jag1 was expressed in PA6 cells and showed demonstrated that the ability for the cells to differentiate was interrupted by the Notch signalling inhibition pathway. <ref><pubmed>22558462</pubmed></ref><br />
|-<br />
| 2014<br />
| Breakthrough in the applications of the Notch signalling pathway. Evidence emerged showing an association between the Notch signalling pathway and gastric cancer and found that Notch1 and Notch2 pathways have been activated in gastric cancer.<ref><pubmed>25083094</pubmed></ref> <br />
|}<br />
<br />
===Overview of Molecular Mechanisms===<br />
Mammals possess a total of four ''Notch'' genes, with five genes for encoding the associated ligands, Delta-like and Jagged. The ''Notch'' genes each code for a single transmembrane receptor. Extracellularly, it contains epidermal growth factor (EGF)-like repeats for ligand interaction and Lin-12-Notch (LN) repeats for regulating the interactions between the extracellular and intracellular regions. Intracellularly, Notch has seven ankyrin (ANK) repeats and a transactivation domain (TAD), as well as a proline, glutamine, serine, threonine-rich (PEST) domain for degradation of Notch.<br />
<br><br><br />
[[File:Notch structure cartoon.jpg|thumb|700px|center|'''The structure of the Notch receptor.'''<ref name="PMID19255248"/> Extracellularly there are epidermal growth factor (EGF)-like repeats and Lin-12-Notch repeats (LNRs). The Notch intracellular domain (NICD) is made up of a rRBP-Jkappa-associated module (RAM) domain, ankyrin (ANK) repeats, and a proline, glutamine, serine, threonine-rich (PEST) domain. There are three sites for cleavage by enzymes: S1, S2, and S3/S4.]]<br />
<br />
====Canonical pathway====<br />
[[File:Overview of Notch signalling.png|thumb|500px|'''Summary of canonical Notch signalling.''' The interaction between Delta-like or Serrate ligands (DSL) and the Notch receptor on an adjacent cell initiates proteolytic cleavage of Notch and the release of the Notch intracellular domain (NICD). The NICD is then transported to the nucleus where it can induce transcription of Notch target genes by binding to specific proteins (MAM, CSL).<ref><pubmed>27404588</pubmed></ref>]]<br />
The canonical Notch pathway is unique in that it involves direct interaction between adjacent cells, as opposed to paracrine signalling, because both the Notch ligands and Notch receptors are transmembrane proteins found in the cell membrane. Furthermore, the lack of a secondary messenger or amplification process means that the Notch pathway has limited opportunities for regulation and must therefore be tightly controlled. Depending on its developmental and cellular context, activation or inhibition of the pathway can result in a variety of cellular responses, including cell death, proliferation, or differentiation.<ref name="Introduction to Notch Signalling">Yamamoto, S., Schulze, K.L. & Bellen, H.J. (2014). Introduction to Notch Signalling. ''Notch Signaling: Methods and Protocols''. Methods in Molecular Biology: 1187</ref><br />
<br><br><br />
Four Notch proteins are involved in the canonical pathway. NOTCH1 to NOTCH4 are single transmembrane receptors and can interact with a variety of ligands, including NOTCH ligands (e.g. Delta ligands) and Serrate ligands. There are three Delta ligands (Dll1, Dll3, and Dll4) and two Serrate ligands (Jagged1 and Jagged2) present in mammals.<ref name="Introduction to Notch Signalling"/> The binding between the Notch receptor and the ligand on the adjacent cell induces the release of the Notch intracellular domain (NICD) via a sequence of proteolytic reactions.<ref name="The Developing Human"/> Cell-cell interaction is therefore critical in the process of triggering Notch signalling.<br />
<br><br><br />
The interaction on the cell surface between Notch and its ligand on an adjacent cell causes the extracellular metalloprotease site (S2 site) to be exposed. The S2 site is then cleaved by transmembrane proteases belonging to the a disintegrin and metalloproteinase/tumour necrosis factor α converting enzyme (ADAM/TACE) family. The remaining Notch fragment subsequently undergoes two more intramembranous cleavages at the S3/S4 sites by the γ-secretase complex. Finally, the NICD is released and enters the nucleus to interact with CSL (CBF1, Suppressor of Hairless, Lag-1) and Mastermind-like proteins (MAMLs). CSL is a DNA-binding protein that acts as a transcription factor by forming repressor or activator complexes; in the absence of the NCID, CSL is bound to corepressor proteins (CoR) that prevent transcription of Notch target genes. MAMLs are transcriptional co-activators that are required for transcription of the target genes, hence they are involved in the regulation of the pathway.<ref name=PMID10075488/><ref name="Introduction to Notch Signalling"/> To stop signalling, the NICD is phosphorylated by kinases and ubiquitinated by E3 ubiquitin ligases, which results in proteasome mediated degradation and subsequent termination of the signal.<ref name="Introduction to Notch Signalling"/><br />
<br><br><br />
<br />
====Non-canonical pathway====<br />
Immense research has been carried out on the canonical Notch pathway and its members are well known. While canonical notch ligands control most of the known Notch signalling, a group of structurally distinct non-canonical ligands exist which activate Notch and its pleiotropic effects. Notch can non-canonically carry out its functions by post-translationally targeting Wnt/β-catenin signalling. This type of signalling is CSL-independent and can also work independently of ligands. Some genes are affected by the non-canonical Notch signalling, however their mediators in most cases are unknown. Notch binds and titrates levels of active β-catenin. Therefore, active β-catenin activity may serve as a useful readout for non-canonical Notch signals.<ref name="PMID22397947">As reviewed by <pubmed>22397947</pubmed></ref> <br />
<br />
Recent research has shown that Notch signalling plays crucial roles for cellular differentiation during development through γ-secretase-dependent intramembrane proteolysis followed by transcription of target genes. Hayashi et al. (2016) uncovered a ligand-dependent but γ-secretase-independent, non-canonical Notch signalling involved in presynaptic protein expression in postmitotic neurons.<ref name="PMID27040987"><pubmed>27040987</pubmed></ref><br />
<br><br><br />
<br />
====Transcriptional regulation of Notch signalling====<br />
A number of genes have been found to act as modulators of Notch signalling by modifying the ability of Notch to interact with its ligands. These include proteins acting extracellularly (Fringe, Brainiac, Egghead, Scabrous, Wingless), proteins acting at the cell membrane (Big brain), proteins acting intracellularly (Numb, Sanpodo, Disabled, Deltex, Dishevelled), and proteins acting within the nucleus (Hairless, EMB-5, Strawberry notch).<ref name="PMID9892565">As reviewed by <pubmed>9892565</pubmed></ref><br />
<br />
In ''Drosophila melanogaster'', it has been seen that ''fringe'' is able to affect the ability of Notch to be activated by the Serrate and Delta ligands. Specifically in the ''Drosophila'' wing, it was observed that Serrate did not interact with Notch in specific areas due to the action of ''fringe''<ref><pubmed>9247339</pubmed></ref>. Fringe is not required for initial Notch signalling, but is thought to be important for signalling processes when Notch activation occurs along the borders between distinct cell populations. Research suggests that Fringe specifically affects the binding between Notch and its ligands, rather than an activation step separate or subsequent to ligand binding. The ''brainiac'' and ''egghead'' genes are thought to either influence the production of a Notch ligand or act as substitute ligands themselves.<ref name="PMID9892565"/><br />
<br><br><br />
<br />
====Examples of Proteins Involved in Interaction with the Notch Intracellular Domain <small>(adapted from Table 3<ref name="PMID21828089"/>)</small>====<br />
{| class="pretty table"<br />
|-bgcolor="A3BFB1" <br />
| '''Protein'''<br />
| '''Interaction with NICD'''<br />
|-bgcolor="F5FFFA"<br />
| Adenamatous polyposis coli (Apc)<br />
| Controls Notch trafficking<br />
|-<br />
| Cyclin-dependant kinase 8 (CDK8)<br />
| Phosphorylates NICD to make it a substrate for ubiquitylation and degradation<br />
|-bgcolor="F5FFFA"<br />
| CBF1, Su(H) and LAG-1/Recombination signal binding protein for immunoglobulin kappa J region (CSL/RBP-J)<br />
| Main canonical transcriptional co-factor for NICD<br />
|-<br />
| Cyclin C (CycC)<br />
| Targets NICD for phosphorylation to make it a substrate for ubiquitylation and degradation<br />
|-bgcolor="F5FFFA"<br />
| Dishevelled (Dsh/Dvl)<br />
| Controls ligand-independent Notch trafficking; inhibits canonical Notch signalling<br />
|-<br />
| Deltex-1-4 (Dtx1-4)<br />
| Controls Notch ubiquitylation, processing, and internalisation<br />
|-bgcolor="F5FFFA"<br />
| Itchy, E3 ubiquitin protein ligase (Itch)<br />
| Promotes ubiquitylation of NICD<br />
|-<br />
| Mastermind-like 1/2 (Maml1/2)<br />
| Co-activator for NICD/CSL<br />
|-bgcolor="F5FFFA"<br />
| Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-ϰb)<br />
| NICD blocks NF-ϰb transcription of NF-ϰb target genes through binding to p50/cRel<br>NICD enhances NF-ϰb transcription of target genes by retaining NF-ϰb in the nucleus<br />
|-<br />
| Numb homolog (Numb)<br />
| Suppresses Notch signaling by recruiting E3 ubiquitin ligases to ubiquitylate Notch<br>Controls Notch trafficking during asymmetric cell division<br />
|-bgcolor="F5FFFA"<br />
| Smad family members (SMAD)<br />
| Smads enhance Notch signalling; Notch fine-tunes signalling through Smads<br />
|}<br />
<br><br />
<br />
===Roles in Embryonic Development===<br />
The phylogenetically conserved Notch signalling pathway plays a crucial role in the development of multiple organ systems, and is a major regulator of stem cell fate. It is responsible for the regulation of the transcription of a number of signalling molecules, such as ''MyoD'', ''Mash1'' and ''GATA2'', which are genes controlling the fate of myogenic, neurogenic and haematopoietic stem cells, respectively. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> The following subsections will further elucidate the vital roles of Notch signalling during normal embryonic development. If you would like to better understand human embryonic development before reading this section, [https://embryology.med.unsw.edu.au/embryology/index.php/Embryonic_Development| this page] serves as a great resource. <br />
<br><br><br />
<br />
====Cardiovascular====<br />
<br />
If you would like to generally learn about and become familiar with cardiac development in the embryo before reading this section, click [https://embryology.med.unsw.edu.au/embryology/index.php/ANAT2341_Lab_11_-_Heart here]!<br />
<br />
'''Cardiomyocyte Specification and Differentiation'''<br />
<br />
Expression during the appropriate window of the timeline of embryogenesis of Notch receptors, ligands and downstream effector molecules elucidates a role for the Notch pathway in the earliest stages of cardiac development. It has been found to restrict the expression of specific cardiogenic genes in a spatiotemporal manner and regulate cardiac field specification as early as during gastrulation. <ref name=PMID19580804><pubmed>19580804</pubmed></ref> Interestingly, Notch has been found to play both suppressive and promoting roles in cardiogenesis.<br />
<br />
For example, it has been shown that Notch suppresses cardiomyocyte cell fate specification during early cardiogenesis. This has been demonstrated through studies such as that carried out by Rones and colleagues (2000), which used activation and inhibition of Notch signaling in Xenopus. <ref name=PMID10934030><pubmed>10934030</pubmed></ref><br />
<br />
On the other hand, studies such as that by Boni et al. (2008) have found that Notch signalling may also promote myogenesis from cardiac progenitor cells. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> Cardiogenesis has also been promoted by downregulating Notch-1 activity in stem cells of embryos (Nemir et al., 2006).<ref name=PMID16690879><pubmed>16690879</pubmed></ref><br />
<br />
Despite the understanding that Notch signalling is crucial to embryonic myogenesis, the exact molecular mechanism remains elusive. Research by Buas and colleagues (2010) has explored such mechanisms by studying the Notch target, Hey1, which is known to suppress myogenic differentiation. They concluded that this inhibitory function of Hey1 is primarily mediated through binding near to myogenin and Mef2C promoters, which leads to cessation of target gene expression. <ref name=PMID19917614><pubmed>19917614</pubmed></ref><br />
<br />
[[File:Notch CVS simple diagram.png|thumb|500px|right|alt=Simplified Scheme of the Roles of Notch in Cardiac Development|'''Simplified Scheme of the Roles of Notch in Cardiac Development.''' Notch has been found to restrict the expression of specific cardiogenic genes in a spatiotemporal manner and regulate cardiac field specification early in development. Further after cardiac differentiation, Notch influences development of the AVC (atrioventricular canal), cardiac valves, ventricular trabeculae and the cardiac outflow tract. (This student-drawn image is based upon Figure 2 in the 2014 review by Zhou and Liu: [https://www.ncbi.nlm.nih.gov/pubmed/24345875 ''Role of Notch signaling in the mammalian heart.'']<ref name=PMID24345875><pubmed>24345875</pubmed></ref>)]]<br />
<br />
'''Development of the Atrioventricular Canal'''<br />
<br />
A study by Rutenberg et al. (2006) and another by Kokubo et al. (2007) implicate a role for Notch signaling in the region between the atria and the ventricles of the heart (the atrioventricular canal, or AVC).<ref name=PMID17021042><pubmed>17021042</pubmed></ref> <ref name=PMID17259303><pubmed>17259303</pubmed></ref> They used chicken and mouse models, respectively, to show that other signalling factors, ''Bmp2'' and ''Tbx2'', are restricted to the AVC region by Notch signalling during development. <br />
<br />
Furthermore, Watanabe and colleagues (2006) showed that deletion of Notch targets increases ''Bmp2'' expression and expansion of the AVC tissue, however other, non-Notch restrictive factors involved in AVC development are likely to exist.<ref name=PMID16554359><pubmed>16554359</pubmed></ref> <br />
<br />
'''Heart Valve Development'''<br />
<br />
In order for the heart valve to properly form in the embryo, endocardial to mesenchymal transformation (EMT) must occur. The Notch pathway, alongside Wnt and Bmp, has been found to regulate the process of EMT, defects in which can lead to congenital heart valve disease. Interestingly, Timmerman and colleagues (2004) demonstrated that this role of Notch may also promote oncogenic transformation. This team also showed that embryos exhibited abortive endocardial EMT if they were deficient in Notch signalling components in vivo and in vitro. <ref name=PMID14701881><pubmed>14701881</pubmed></ref> <br />
<br />
A more recent paper by Wang et al. (2013) further explored the underlying signalling processes and interrelationships of molecules that impact EMT. They found that Jagged1-Notch1 signalling in cells of the endocardium potentiates expression of Wnt4, which in turn carries out paracrine action on adjacent AVC tissue to upregulate Bmp2 expression and thus signal EMT. <ref name=PMID23560082><pubmed>23560082</pubmed></ref><br />
<br />
'''Trabeculation'''<br />
<br />
Trabeculation is the initial process of ventricular chamber development that forms a series of cardiomyocyte projections within the lumens of the ventricles of the heart (called trabeculae). Grego-Bessa and colleagues (2007) addressed the roles Notch plays in trabeculation through ''RBPJk'' (the gene product of which interacts with Notch) and ''Notch1'' gene manipulation. Mutants of these two genes showed perturbed expression and signalling of ''EphrinB2'', ''NRG1'' and ''BMP10'', alongside reduced proliferation of myocardiocytes. This research ultimately suggested that ''EphrinB2'' is a direct target of Notch in the endocardium that simultaneously requires the Notch-dependent action of BMP10 and NRG1 in order for ventricular myocardium proliferation and differentiation to occur normally. <ref name=PMID17336907><pubmed>17336907</pubmed></ref> Furthermore, the important process of trabeculation has recently been shown to be controlled by sequential Notch activation by an investigation by D’Amato et al. (2015). <ref name=PMID26641715><pubmed>26641715</pubmed></ref><br />
<br />
'''Development of the Outflow Tract'''<br />
<br />
About one third of congenital heart defects include malformations in the outflow tract which include the aorta, pulmonary arteries, aortic arch and ductus arteriosus. During cardiogenesis, neural crest cells interact with second heart field myocardium and endocardial mesenchyme. <ref><pubmed>20201902</pubmed></ref> <br />
Studies involving neurogenesis demonstrated the sensitivity of Notch signaling to temporal and spatial cues and showed the early Notch signaling initially controls the number of cells with a neurogenic fate and later dictates the lineage decision of neural versus glial cell fate. <ref><pubmed>16429119</pubmed></ref><br />
Neural crest precursors for ideal patterning of the outflow tract are required in the Notch signaling pathway. The use of a dominant negative form of a master mind like protein (MAML) which has shown to be a pan Notch inhibitor in neural crest cells inactivates Notch signaling. This results in congenital heart defects like pulmonary artery stenosis and aortic arch patterning defects associated with defects in smooth muscle formation. <ref><pubmed> 17273555 </pubmed></ref><br />
Part of the phenotype in defective neural crest cells is attributed to loss of Notch2 signalling as Notch2 inactivation in these cells produces small caliber aortas and pulmonary arteries because of defects in smooth muscle. <ref><pubmed> 18330927 </pubmed></ref><br />
Jagged1 is the ligand involved which signals to Notch on neural crest cell surfaces to induce vascular smooth muscle cell differentiation. <ref><pubmed> 18245384 </pubmed></ref><br />
Mutations in both JAGGED1 and NOTCH2 genes have been known to cause Alagille syndrome, further substantiating the importance of this pathway in proper formation of the outflow tract. <ref><pubmed> 16575836 </pubmed></ref><br />
<br />
Another study by Garg stresses the importance of Notch signaling in the outflow tract region. NOTCH1 mutations were seen in patients with aortic stenosis. Aortic stenosis results from the calcification of the aortic valve and is quite common in adults. However, in children, this may result in failure of the left ventricle to develop properly. NOTCH1 haploinsufficiency is also linked to early calcification and bicuspid aortic valve disease. This could be due to an early induction of Runx2 through the HRT genes.<br />
<ref><pubmed> 16025100 </pubmed></ref><br />
<br />
<br><br><br />
<br />
====Central Nervous System====<br />
<br />
If you would like to generally learn about and become familiar with neural development in the embryo before reading this section, click [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Neural_Development here]!<br />
<br />
[[File:Notch CNS simple diagram.png|thumb|450px|right|alt=Simplified Diagram of Roles of Notch in Neuronal Differentiation|'''Simplified Diagram of Roles of Notch in Neuronal Differentiation'''. Notch influences the differentiation of embryonic stem cells into neural cells via signalling with RBP (recombining binding protein), cyclin D1 and Hes1. (This student-drawn image is based upon Figure 1 from Chuang, Tung and Lin's 2015 review: [https://www.ncbi.nlm.nih.gov/pubmed/25815127 ''Neural differentiation from embryonic stem cells in vitro: An overview of the signaling pathways'']<ref name="PMID25815127"><pubmed>25815127</pubmed></ref>)]]<br />
'''Early Neural Differentiation'''<br />
<br />
Notch plays a major role in promoting neural commitment of cells. Lowell and colleagues (2011) used genetic manipulation to discover that the phenotype of stem cells is not affected by constitutively activated Notch in mouse embryonic stem cells (mESCs), however, interfering with Notch signalling -for example by pharmacological means- did impede neural fate determination. This role required Notch signalling via fibroblast growth factor (FGF) receptors. Furthermore, the conservation of the Notch signalling pathway within pluripotent stem cells is implied due to the existence of Notch ligands in stromal cells in human embryonic stem cells (hESCs) that induce neural differentiation. <ref name=PMID16594731><pubmed>16594731</pubmed></ref><br />
<br />
Das and colleagues (2010) manipulated Notch protein levels during specific stages of neural differentiation and found that if Notch signalling pathways were activated during day 3 of neural development for 6 hours, cell proliferation was dramatically enhanced. This was attributed to the induction by Notch of cyclin D1 expression. Without Notch signalling during neural development, there was reduced cyclin D1 levels. Manipulation of mESCs to express a dominant negative form of cyclin D1 resulted in abrogation of cell proliferation stimulated by Notch. Overall these results imply a temporally-specific role for Notch in CNS development, and that it requires cyclin D1 as a signalling molecule.<ref name=PMID20887720><pubmed>20887720</pubmed></ref><br />
<br />
Hes1 has also been shown to play a Notch-mediated role in neural progenitor maintenance, which is essential for proper development since cells need to proliferate only during specific periods in the embryo for the correct number, cell type and function to result. Shimojo, Ohtsuka and Kageyama (2008) used real time imaging in mice to show that Notch induces oscillatory expression of ''Hes1'' and other Notch target genes to maintain the complex temporal organisation of events in neural development. They concluded that further research could elucidate more about Hes1 oscillations in regards to neural progenitor maintenance, proliferation and differentiation <ref name=PMID18400163><pubmed>18400163</pubmed></ref>.<br />
<br />
Lastly, as well as influencing neural progenitor differentiation, it has been found that Notch also impacts the development and maintenance of polarised neural structures in the embryo. This was concluded from a knockout study in mice that elucidated a role for RBP (recombining binding protein), downstream of Notch, in modulating neural differentiation and maintaining rosette structure (an experimental ''in vitro'' correlate used for neural tube development) <ref name=PMID23675446><pubmed>23675446</pubmed></ref>. The researchers concluded that RBP knockouts lacked canonical Notch signalling and as a result showed multiple neurulation defects.<br />
<br><br><br />
<br />
====Other Systems====<br />
<br />
As aforementioned, Notch plays a wide array of roles in embryonic development, the follow table summarises these roles by each organ system:<br />
<br />
<big>Summary Table of Examples of Notch Signalling in Developmental Processes</big> <small>(adapted from Table 1<ref name="PMID21828089">As reviewed by <pubmed>21828089</pubmed></ref>)</small><br />
{| class="pretty table"<br />
|-bgcolor="CEDFF2"<br />
| '''Organ/Tissue'''<br />
| '''Processes regulated by Notch'''<br />
|-bgcolor="F5FAFF" <br />
| Brain<br />
| Controls the balance between gliogenesis and neurogenesis; stem cell maintenance<ref><pubmed>21262462</pubmed></ref><ref>As reviewed by <pubmed>20816397</pubmed></ref>; organisation and maintenance of polarity during early development<ref name="PMID23675446"/><br />
|-<br />
| Craniofacial structures<br />
| Palate morphogenesis: loss of Notch signalling results in cleft palate, fusion of the tongue with the palatal shelves, and other craniofacial defects; also involved in tooth development<br />
|-bgcolor="F5FAFF"<br />
| Ear<br />
| Defines the presumptive sensory epithelium; determines hair cell and supporting cell fates<br />
|-<br />
| Esophagus<br />
| Regulates esophageal epithelial homeostasis<br />
|-bgcolor="F5FAFF"<br />
| Heart<br />
| Cardiac patterning, cardiomyocyte differentiation, valve development, ventricular trabeculation, outflow tract development<br />
|-<br />
| Intestine<br />
| Controls proliferation and differentiation, including absorptive vs. secretory cell fates<br />
|-bgcolor="F5FAFF"<br />
| Limbs<br />
| Apical ectodermal ridge (AER) formation and digit morphogenesis, especially regulation of apoptosis<br />
|-<br />
| Lungs<br />
| Lateral inhibition between tracheal cells prevents extra cells from assuming the lead position during tracheal branching morphogenesis<br />
|-bgcolor="F5FAFF"<br />
| Neural crest<br />
| Controls patterning of neural crest precursors for the outflow tract region of the heart; regulates the transition from Schwann cell precursor to Schwann cell, controls Schwann cell proliferation and inhibits myelination; controls melanocyte stem cell maintenance<br />
|-<br />
| Pancreas<br />
| Specifies endocrine cell differentiation through lateral inhibition: endocrine lineage cells inhibit endocrine differentiation of their neighboring cells; maintains pancreatic endocrine precursor cells, inhibits terminal acinar cell differentiation; controls pancreatic epithelium branching and bud size<br />
|-bgcolor="F5FAFF"<br />
| Skin<br />
| Regulates cell adhesion, control of proliferation, hair follicle or feather papillae differentiation and homeostasis<br />
|-<br />
| Thyroid<br />
| Regulates the numbers of thyrocyte and C-cell progenitors and regulates differentiation and endocrine function of thyrocytes and C-cells<ref><pubmed>21364918</pubmed></ref><br />
|-bgcolor="F5FAFF"<br />
| Vasculature<br />
| Regulates arteriovenous specification and differentiation in endothelial cells and vascular smooth muscle cells; regulates blood vessel sprouting and branching<br />
|}<br />
<br />
====Quiz Your Notch-Knowledge on Embryonic Development!====<br />
<br />
<quiz display=simple><br />
<br />
{ In the development of which organ does Notch exert lateral inhibition to differentiate endocrine cells?<br />
|type="()"}<br />
- &nbsp; The heart<br />
- &nbsp; The central nervous system<br />
- &nbsp; The skin<br />
+ &nbsp; The pancreas<br />
|| Remember, Notch signals endocrine lineage cells of the developing pancreas to inhibit endocrine differentiation of their neighbouring cells, known as lateral inhibition. Notch plays various roles in the heart, central nervous system and skin, but not in this way. <br />
</quiz><br />
<br><br />
<br />
===Roles in Animal Development===<br />
The Notch signalling pathway doesn't just play a significant role in human development, but also affects events such as neurogenesis and myogenesis in some animals (thus why these animals are often used as models for human development in research!). Read below for information on some of these roles for Notch.<br />
<br><br><br />
<br />
[[File:Notch animals.png|thumb|450px|right|alt=Animals Whose Developmental Processes are Affected by Notch.|'''Animals Whose Developmental Processes are Affected by Notch.''' This is a simplified representation of a few examples of the animals (Drosophila flies<ref name=PMID21447553><pubmed>21447553</pubmed></ref>, C. elegans<ref name=PMID18599512><pubmed>18599512</pubmed></ref>, and the zebrafish<ref><pubmed>23840804</pubmed></ref>) in which development is influenced by the Notch signalling pathway, and their scientific names.]]<br />
<br />
====''Drosophila melanogaster''====<br />
<br />
'''(The Fly)'''<br />
<br />
Unlike the four Notch paralogs in humans, only one Notch homolog is present in ''Drosophila''.<ref name="Introduction to Notch Signalling"/><br />
<br />
Both canonical and non-canonical Notch signalling are involved in the structural and physiological responses and functional plasticity of olfactory receptor neurons in reaction to prolonged odour exposure.<ref><pubmed>26986723</pubmed></ref><ref><pubmed>26011623</pubmed></ref> Research has also shown that Notch is crucial for the formation of longitudinal connections in the Drosophila CNS. Kuzina, Song, and Giniger (2011) created temperature-sensitive mutations of Notch genes that prevented the development of mature longitudinal axon tracts. Additionally, it was found that the Notch phenotype appears at the earliest stages of the development of longitudinal connections in the CNS by observing early stage 13 embryos.<ref name=PMID21447553><pubmed>21447553</pubmed></ref><br />
<br><br><br />
<br />
====''Caenorhabditis elegans''====<br />
<br />
'''(The Worm)'''<br />
<br />
The Notch pathway in ''C. elegans'' occurs throughout development in populations of equipotent cells for neuronal function in postmitotic differentiated neurons. In these postmitotic neurons, there is a specialised post-embryonic development stage knows as 'dauer'. The Notch pathway is activated when cell signalling downstream of the developmental decision enter dauer. The Notch receptor glp-1 and the ligand lag-2 are expressed in the dauer stage and aid in maintaining this stage. Another Notch receptor, lin-12, functions upstream of insulin signalling components to promote conditions for growth and enhance dauer recovery. <ref name=PMID18599512><pubmed>18599512</pubmed></ref><br />
<br><br><br />
<br />
====''Danio rerio''====<br />
<br />
'''(The Zebrafish)'''<br />
<br />
The expression of Notch in the myogenic region and apical ectodermal ridge (AER) of the developing zebrafish fin is similar to what has been observed in developing chicken and mouse limbs, which shows how highly conserved the role of Notch signalling is in the development of appendages in vertebrates. During zebrafish embryogenesis, the timing and positioning of fin formation are dependent on Notch signalling. Notch is also involved in the actual processes of fin formation, such as AER signalling, chondrogenic differentiation, and myogenesis. In zebrafish embryos with defective Notch signalling, it was observed that the skeletal muscle fibres were thin and fragmented and the structure of the sarcomeres was significantly compromised. <ref name="PMID23840804"><pubmed>23840804</pubmed></ref><br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Expand this for an image from this research study</big><br />
|-<br />
|[[File:Abnormal pectoral fins are formed in Notch signalling disrupted larvae.jpg|thumb|450px|right|alt=Abnormal pectoral fins are formed in Notch signalling disrupted larvae|'''Abnormal pectoral fins are formed in Notch signalling disrupted larvae.''' (A–F) Live pictures of 5 dpf larvae. (A’) A pectoral fin from a sibling embryo showing the cartilaginous endoskeletal disc with individualized cells surrounded by thin matrix deposits, the fin fold and the chleitrum (n = 17) (E, E’). A similar pectoral fin was found in a DMSO-treated embryo (n = 9). Pectoral fins of Notch signalling disrupted embryos such as mibta52b (n = 18) (B, B’), jagged2 (n = 10) (C, C’) and Su(H)1+2 (n = 12) (D, D’) morphants and DAPT-treated embryos (n = 10) (F, F’) showing disorganized endoskeletal disc cells. cl, chleitrum; ed, endoskeletal disc; ff, fin fold.<ref name="PMID23840804"/>]]<br />
|}<br />
<br><br><br />
<br />
====Quiz Your Notch-Knowledge on Animal Development!====<br />
<br />
<quiz display=simple><br />
<br />
{In which animal (as described in this section) has it been shown that defective notch signalling leads to thinning and fragmentation of skeletal muscle fibres?<br />
|type="()"}<br />
- &nbsp; Drosophila melanogaster<br />
- &nbsp; I don't know!<br />
- &nbsp; Caenorhabditis elegans<br />
+ &nbsp; Danio rerio<br />
|| Remember, it was observed in one study that the skeletal muscle fibres of zebrafish (Danio rerio) were thin and fragmented and the structure of their sarcomeres were significantly compromised.<ref><pubmed>23840804</pubmed></ref> <br />
</quiz><br />
<br />
===Summary of Functions of Proteins Involved in Notch Signalling <small>(adapted from Table 1<ref name="PMID17761886"><pubmed>17761886</pubmed></ref>)</small>===<br />
{| class="pretty table"<br />
|-bgcolor="a3bfb1"<br />
| '''Mammals'''<br />
| '''''Drosophila'''''<br />
| '''''C.elegans'''''<br />
| '''Function'''<br />
|-bgcolor="F5FFFA" <br />
| Notch 1-4<br />
| Notch<br />
| Lin-12, Glp-1<br />
| Single transmembrane receptor and transcription factor<br />
|-<br />
| Delta 1, Delta3-4, Jagged1-2<br />
| Delta, Serrate<br />
| APX-1, LAG-2, ARG-1, DSL-1<br />
| Single transmembrane ligands of the Notch receptor<br />
|-bgcolor="F5FFFA" <br />
| CBF1/RBPJK<br>Mastermind1-3<br />
| Su(H)<br>Mastermind<br />
| Lag-1<br>Lag-3<br />
| DNA-binding transcription factor<br>Transcriptional co-activator<br />
|-<br />
| Lunatic, manic, and radical Fringe<br />
| Fringe<br />
|<br />
| Modifies both Notch and its ligands<br />
|-bgcolor="F5FFFA" <br />
| ADAM10, ADAM17<br />
| Kuzbanian, Kuzbanian-like, TACE<br />
| SUP-17, ADM-4<br />
| Metalloproteases targeting S2 Notch cleavage sites<br />
|-<br />
| Presenilin 1-2, nicastrin, APH1, PEN2<br />
| Presenilin, nicastrin, APH1, PEN2<br />
| SEL-12, APH-1, APH-2, PEN2<br />
| Proteins of the γ-secretase complex, which targets Notch S3 and S4 cleavage sites<br />
|-bgcolor="F5FFFA" <br />
| Mind bomb, skeletrophin, neuralized 1-2<br />
| Mind bomb 1-2, neuralized<br />
| Y47D3A.22<br />
| E3 ubiquitin-protein ligases that targets Delta and Jagged/Serrate and regulate their endocytosis<br />
|}<br />
<br><br />
<br />
===Abnormalities in Notch Signalling===<br />
Mutations in Notch genes and hence defects in Notch signalling have been implicated in the pathogenesis of several inherited diseases in humans.<ref name="PMID23729744">As reviewed by <pubmed>23729744</pubmed></ref><ref name="PMID22306179">As reviewed by <pubmed>22306179</pubmed></ref> The diseases listed in this summary table are only a few examples and are described in more detail below.<br />
<br><br />
<br />
{| class="pretty table"<br />
|-bgcolor="CEDFF2" <br />
| '''Disease'''<br />
| '''Gene'''<br />
| '''Phenotype'''<br />
|-bgcolor="F5FAFF" <br />
| Alagille syndrome ([http://omim.org/entry/118450 OMIM118450], [http://omim.org/entry/610205 OMIM610205])<br />
| ''JAG1'', ''NOTCH2''<br />
| Developmental abnormalities of the heart, liver, eye, and skeleton. Neonatal jaundice and cholestasis are early symptoms.<br />
|-<br />
| CADASIL ([http://omim.org/entry/125310 OMIM125310])<br />
| ''NOTCH3''<br />
| Autosomal vascular disorders linked to ischemic strokes, dementia, and premature death.<br />
|-bgcolor="F5FAFF"<br />
| T-cell acute lymphoblastic leukaemia ([http://omim.org/entry/613065 OMIM613065])<br />
| ''NOTCH1'' (mutation in heterodimerization domain or PEST domain)<br />
| Tumour derived from T-cell progenitors. Symptoms include anaemia and enlargement of lymph nodes in the liver and/or spleen.<br />
|-<br />
| Spondylocostal dysostosis ([http://omim.org/entry/122600 OMIM122600])<br />
| ''DLL3'', Lunatic fringe<br />
| Vertebral segmentation defects as well as rib abnormalities.<br />
|}<br />
<br />
====Alagille Syndrome====<br />
Alagille syndrome (AGS) is an autosomal dominant, multisystem disorder that mainly affects the liver, heart, and kidney. Diagnostic characteristics of the disease include liver disease, cardiac disease, vertebral defects, eye conditions, and facial features, as well as renal and vascular abnormalities.<ref>As reviewed by <pubmed>26548814</pubmed></ref> Two variants of AGS, type 1 and type 2, have been identified, and each is related to different defects in the Notch pathway. In clinically diagnosed cases of AGS type 1 (which accounts for approximately 97% of all cases of AGS), a mutation in the gene encoding the Notch ligand Jagged1 (Jag1) has been identified as a contributing factor.<ref>As reviewed by <pubmed>11745040</pubmed></ref> In the much rarer AGS type 2, a mutation in the NOTCH2 gene has been implicated in the manifestation of AGS. The mechanisms by which mutations in JAG1 and NOTCH2 lead to pathogenesis of AGS are not well understood, but it is known that normal Notch signalling is important in angiogenesis. Therefore, it is thought that abnormal JAG1 or NOTCH2 will cause disruptions to the pathway that leads to the vascular disorders present in AGS. This is also evidenced by research that JAG1 knockout mice suffer premature death due to vascular defects.<ref>As reviewed by <pubmed>21934706</pubmed></ref> It is possible that AGS caused by a mutation in NOTCH2 alone will lead to a different presentation than AGS patients with mutated JAG1; however, this is still undergoing further research. It is also unclear why AGS type 2 occurs at a significantly lower incidence than AGS type 1.<ref><pubmed>16773578</pubmed></ref><br />
<br><br><br />
<br />
====Spondylocostal Dysostosis====<br />
Spondylocostal Dysostosis (SD) is a collective term for conditions characterised by anomalies relating to rib and spine. The vertebrae are fused and shaped abnormally which can result in scoliosis. Similarly, the ribs may also be fused together or in some cases completely missing. As a result, people with this condition have short trunk dwarfism where their bodies are short in stature but have normal length limbs. Genetic changes are known to cause SD. SD Type 1 is the most prevalent form of this disease which is caused by the mutation in the delta like canonical Notch ligand 3 (DLL3 gene).<ref><pubmed>10742114</pubmed></ref> DLL3 provides the information for making a protein that regulates the Notch signalling pathway. The DLL3 protein in conjunction with the Notch pathway is primarily responsible for preventing the fusion of future vertebrae in a process known as somite segmentation.<ref><pubmed>11236715</pubmed></ref> An interruption in the Notch pathway inhibits the somite segmentation resulting in abnormalities relating to the ribs and spine as seen in SD. 25 percent of SD arise from mutations in the identified genes and further research suggest that other genes involved in the Notch signalling pathway may also be related to SD.<br />
<br><br><br />
<br />
====Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)====<br />
CADASIL is an autosomal-dominant disease of the small to medium-sized arteries, mainly in the brain, that leads to dementia and disability in mid-life. The symptoms, age of onset, and prognosis are variable. Distinguishing symptoms include subcortical ischemic events (60-80% of cases), cognitive impairment (60% of late stage disease), migraines (30-40%), mood disturbances (30%), and apathy (40%).<ref name="PMID21045164"><pubmed>21045164</pubmed></ref><ref name="PMID20301673"><pubmed>20301673</pubmed></ref> Approximately 5-10% of CADASIL patients also experience seizures. The mean age of onset is 45 years of age and the disease duration is between 10–40 years. More than 95% of CADASIL cases present with pathogenic mutations in NOTCH3 (located on chromosome 19p13), specifically the epidermal growth factor-like repeat domain.<ref name="PMID20301673"/><ref><pubmed>24579972</pubmed></ref> The NOTCH3 gene is involved in the normal development of blood vessels in both fetal and adult brains. In adults, NOTCH3 is expressed in the smooth muscle cells of arteries.<ref name="PMID21045164"/> There is currently no effective treatment available for CADASIL.<br />
<br><br><br />
<br />
====Congenital Heart Defects====<br />
<br />
'''Aortic Valve Disease'''<br />
<br />
[[File:Aortic valve disease.jpg|thumb|450px|right|alt=Loss of NOTCH1 expression in proximity to calcific nodules in human aortic valves|'''Loss of NOTCH1 expression in proximity to calcific nodules in human aortic valves.''' (A) Representative sections from control (A,B) and diseased (C-F) aortic valve cusps. (B) is high magnification image of boxed area in (A) and (D,E) are higher magnification of region in (C) while image in (F) shows another calcified aortic valve. Expression of Notch1 intracellular domain (NICD) is found in the thickened fibrosa of diseased aortic valve (C,E) as compared to the acellular fibrosa of control valves (A,B). However, there is significant loss of NICD expression in cells residing adjacent to calcific nodules (D,F). The fibrosa is oriented upward in all panels, and scale bars equal 100 microns (B,D,E,F are at same magnification). Brown signal represents NICD expression while nuclei are counterstained in blue.<ref name="PMID22110751"><pubmed>22110751</pubmed></ref>]]<br />
<br />
Calcification of the aortic valve is a leading cause of adult heart disease. Mutations in NOTCH1 have been found to cause various aortic valve abnormalities, including the development of a bicuspid aortic valve (as opposed to tricuspid) and valve calcification.<br />
<br />
&emsp;&emsp;A study by Garg et al. (2005) looked at mouse embryos and the expression of ''Notch1'' during development. It was found that during normal embryonic development, ''Notch1'' was abundantly expressed in the outflow tract mesenchyme (which develops into the heart valves) and the endocardium, as well as in the endothelial layer and mesenchyme of the aortic valve leaflets at the time of arterial trunk septation. Abnormal ''Notch1'' led to the death of mice from vascular endothelial defects. Garg et al. then investigated whether NOTCH1 was involved in calcium deposition and therefore valve calcification. This is thought to be due to differentiation of valve cells into osteoblast-like cells. This leads to the upregulation of osteopontin, osteocalcin, and other osteoblast-specific genes, which is normally regulated by the transcription factor Runx2. Runx2 is known to be upregulated in animal models of valve calcification. Garg et al. found that Notch1 was capable of repressing Runx2 activation. Heart tissue and vasculature are normally abundant with the hairy-related transcriptional repressors Hrt1 and Hrt2 (also called Hey1 and Hey2), which are normally activated by Notch and are key mediators of the Notch pathway. Hrt1 and Hrt2 were both expressed in the endothelium of the mice aortic valve leaflets, the endocardium, and the vascular endothelium. They were found to inhibit the activation of osteoblast-specific genes by Runx2. It was thought that Hrt proteins can repress Runx2 by physical interaction as well as mediate Notch1 repression of Runx2. Therefore, a defect in Notch will cause upregulation of Runx2, due to the lack of repressor activity by Notch itself and the activation of the repressors Hrt1 and Hrt2. This leads to the expression of osteoblast genes that results in the differentiation of valvular cells into osteoblast-like cells and ultimately causes aortic valve calficiation.<ref><pubmed>16025100</pubmed></ref><br />
<br />
The picture to the right is a histological image of aortic valve disease from a study performed in rats investigating molecular changes that occurred when Notch signalling was suppressed in the aortic valve.<ref name="PMID22110751"/><br />
<br><br><br />
<br />
====Tumourigenesis====<br />
Notch has been shown to be involved in cancer development and can act as both an oncogene and a tumour suppressor gene.<ref>As reviewed by <pubmed>14570040</pubmed></ref><ref name="PMID23729744"/> Defective Notch signalling has been implicated in the pathogenesis of several human cancers, such as acute myelogenous leukemia (overexpression of Jagged1 and Notch1), multiple myeloma (overexpression of Jagged1/2 and Notch1/2), and B-cell–derived Hodgkin lymphoma (overexpression of Jagged1 and Notch1).<ref name="PMID16291593">As reviewed by <pubmed>16291593</pubmed></ref><br />
<br />
Elevated levels of Notch ligand proteins and/or mRNA have been observed in several cancers. Upregulated Jagged1 mRNA has been seen in human pancreatic cancer; Jagged1 protein overexpression has also been studied in prostate, cervix, and brain cancers. Cervical cancers have shown upregulated Jagged2 mRNA. Additionally, elevated Dll1 mRNA has been observed in cervical cancers, as well as in human brain cancers at both Dll1 mRNA and protein levels. Additionally, defective Notch receptor expression has been implicated in cancer as well. For example, elevated Notch1 protein expression has been found in cervical, colon, lung, pancreas, skin, and brain cancers. Protein overexpression of Notch3 and Notch4 has also been seen in malignant melanoma and pancreatic cancer.<ref name="PMID16291593"/><br />
<br />
Interestingly, research has shown that Notch signalling can also have a tumour-suppressive effect. Studies have indicated that Notch signalling can inhibit proliferation and even stimulate apoptosis in malignant B-cells. Furthermore, the Notch1 intracellular domain has also shown the ability to induce growth arrest and apoptosis in Hodgkin lymphoma and multiple myeloma cells.<ref name="PMID16291593"/><br />
<br><br><br />
<br />
'''T-Cell Acute Lymphoblastic Leukaemia'''<br><br />
T-cell acute lymphoblastic leukaemia (T-ALL) is an example of how abnormal Notch signalling can lead to the development of cancer. T-ALL is an aggressive childhood cancer of the immune system's T-cells. The NOTCH1 gene encodes the Notch1 receptor, which is involved in the determination of pluripotent cell progenitors to T-cells and the organisation of these cells in the developing thymus. Activating mutations in the extracellular domain and/or the C-terminal PEST domain of Notch1 have been identified in more than half of all cases of T-ALL.<ref><pubmed>15472075</pubmed></ref><br />
<br><br><br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Other Examples of Roles of Notch in Cancer <small>(adapted from ''Notch in disease''<ref name="PMID23729744"/>)</small><br />
|-<br />
|-bgcolor="a3bfb1"<br />
| '''Gene'''<br />
| '''Role of Notch'''<br />
| '''Disease'''<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br>''NOTCH2''<br />
| Oncogene<br>Tumour suppressor<br />
| Pancreatic ductal adenocarcinoma<br />
|-<br />
| ''NCSTN''<br>''MAML1''<br>''APH1A''<br>''NOTCH2''<br />
| Tumour suppressor<br />
| Chronic myelomonocytic leukaemia<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br />
| Oncogene<br />
| Chronic lymphocytic leukaemia<br />
|-<br />
| Activated NOTCH<br />
| Tumour suppressor<br />
| Hepatocellular carcinoma<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br>''NOTCH2''<br>''NOTCH3''<br />
| Tumour suppressor<br />
| Head and neck squamous cell carcinoma<br />
|-<br />
| NOTCH<br />
| Tumour suppressor<br />
| B-cell acute lymphoblastic leukaemia<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br />
| Oncogene<br />
| Non-small-cell lung cancer<br />
|-<br />
| ''NOTCH1''<br />
| Oncogene<br />
| T-cell acute lymphoblastic leukaemia<br />
|}<br />
<br><br />
<br />
====Quiz Your Notch-Knowledge on Abnormalities in Notch Signalling!====<br />
<br />
<quiz display=simple><br />
{ What is the name for the collection of rib and spine abnormalities that result from interruption in the Notch pathway that leads to inhibition of somite segmentation in the embryo?<br />
|type="()"}<br />
- &nbsp; Alagille Syndrome<br />
- &nbsp; T-cell acute lymphoblastic leukaemia<br />
+ &nbsp; Spondylocostal Dysostosis<br />
- &nbsp; CADASIL<br />
|| Remember, Spondylocostal Dysostosis is a collective term for conditions characterised by anomalies relating to rib and spine. Genetic changes lead to an interruption in the Notch pathway that inhibits the somite segmentation resulting in abnormalities relating to the ribs and spine. Alagille syndrome is an autosomal dominant, multisystem disorder that mainly affects the liver, heart, and kidney. T-cell acute lymphoblastic leukaemia is an aggressive childhood cancer of the immune system's T-cells. CADASIL is an autosomal-dominant disease of the small to medium-sized arteries, mainly in the brain, that leads to dementia and disability in mid-life.<br />
</quiz><br />
<br />
===Current Areas of Research and Future Directions===<br />
Notch has been identified as having a role in the development of several cancers, and therefore research has recently begun investigating the use of Notch inhibitors in cancer treatment.<ref>As reviewed by <pubmed>27732970</pubmed></ref> γ-secretase inhibitors (GSIs), which inhibit the normal cleavage of Notch at the cell membrane and hence NICD release, have been a popular area of research. In the specific case of desmoid tumours, it was observed that treatment GSIs resulted in decreases in NICD and Hes1 expression in the tumour cells. Overall, tumour cell migration and invasion were decreased and cell growth was also inhibited.<ref><pubmed>26349011</pubmed></ref> GSIs have also been shown to have an inhibitory growth effect on pancreatic, breast, and lung cancers, but unfortunately they also produce side effects ''in vivo''.<ref>As reviewed by <pubmed>27688721</pubmed></ref> Therefore continued study into GSIs is required to make them safe for human treatment. Ultimately, with ongoing research, it is possible that the Notch pathway will eventually become an effective therapeutic target for cancers.<br />
<br><br><br />
<br />
<big><b>To search and read recent PubMed research and review articles on Notch, click <u>[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=Notch here]</u>!</b></big><br />
<br><br><br />
<br />
===Want to Read More About Notch?===<br />
The [http://www.omim.org/ OMIM (Online Mendelian Inheritance in Man) database] contains extensive information about the Notch genes and associated proteins and is a great place to go if you want to find out more about the Notch pathway in humans! Click on these links to learn more about the Notch genes that encode the human receptors and ligands:<br />
<li>[http://www.omim.org/entry/190198 NOTCH1] | [http://www.omim.org/entry/600275 NOTCH2] | [http://www.omim.org/entry/600276 NOTCH3] | [http://www.omim.org/entry/164951 NOTCH4]<br />
<li>[http://www.omim.org/entry/601920 JAG1] | [http://www.omim.org/entry/602570 JAG2]<br />
<li>[http://www.omim.org/entry/606582 DLL1] | [http://www.omim.org/entry/602768 DLL3] | [http://www.omim.org/entry/605185 DLL4]<br />
<br><br><br />
<br />
You can also look at these papers for examples of reviews and research papers that reinforce the diversity of how the Notch pathway functions in organisms.<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch influences adult development as well!</big><br />
|-<br />
|Interestingly, Notch does not only play a role in human embryonic development, but has also been found to influence developmental processes after birth. One of these processes is neurogenesis, for example.<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159580/ '''Not(ch) just development: Notch signalling in the adult brain.'''] <br />
<br />
This review explains that the Notch signalling pathway, which is so often regarded as a major molecular player in development, actually has important functions related to neural cells in the adult. As you would have read in the [[#Abnormalities in Notch signalling| Abnormalities in Notch Signalling]] section, Notch abnormalities are involved in a number of diseases, which underlines its importance in maintaining adult brain function. Some highlights of this review are: Figure 2 provides a schematic representation of precise roles Notch activation can play in the adult brain; explanations of the ways that Notch influences brain plasticity; and the discussion of conflicting results of studies exploring the role of Notch in stroke recovery.<ref name=PMID21505516><pubmed>21505516</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch Modulation for Therapy</big><br />
|-<br />
|As you would have read in the [[#Abnormalities in Notch signalling| Abnormalities in Notch Signalling]] section, Notch can play different roles in cancer development. An interesting review further elucidates that modulation of Notch signalling is actually being investigated as a potential target for cancer therapy:<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704338/ '''Targeting the Notch signaling pathway in cancer therapeutics'''] <br />
<br />
This articles focuses on reviewing data emerging from recent research, explaining how Notch contributes to the development of a number of cancers, and then outlining the current focuses of investigations into how to therapeutically manipulate the Notch pathway. Some highlights from this review are: the detailed description of how Notch interacts with other signalling pathways such as Wnt and the signalling cytokine Interleukin-6; explanations of the seemingly conflicting roles of Notch as a tumour promoter and suppressor; and discussion of the findings of various Notch-related studies in cancer stem cells.<ref name=PMID26767041><pubmed>26767041</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch influences reproduction in worker honey bees!</big><br />
|-<br />
| In our [[#Roles in Animal Development| Roles in Animal Development]] section we discussed Notch in relation to a number of animals, however one that we did not cover was the worker honey bee, or ''Apis mellifera''. A recent study shows that Notch also plays a role in these honeybees!<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976197/ '''Notch signalling mediates reproductive constraint in the adult worker honeybee.'''] <br />
<br />
This research paper essentially concludes that in the worker honeybee Notch signalling constrains reproduction between males and females; they were the first team to elucidate a molecular mechanism underlying the link between adult ovary activity in bees and the presence of the queen bee. Some highlights from this unique and interesting study are: the background explanation that female worker bees have suppressed activity due to pheromones produced by the queen; the finding that Notch plays a part in this inactivation of reproductivity; and the discussion about social control of reproduction and evolution.<ref name=PMID27485026><pubmed>27485026</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch signalling is involved in embryo implantation!</big><br />
|-<br />
| Notch is essential for many developmental embryonic processes, as described in our [[#Roles in Embryonic Development|Roles in Embryonic Development]] section. Interestingly, research has shown that Notch signalling also has an important role in the initial process of establishing a successful pregnancy. Specifically, normal Notch signalling has been seen to be a critical factor in fetal-maternal communication during implantation and placentation. (To read more about these processes, go to these pages on [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Week_1_and_2_Development Weeks 1-2] and [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Week_3_Development Week 3] of development.)<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/24357662 '''Fetal-maternal communication: the role of Notch signalling in embryo implantation.''']<ref>As reviewed by <pubmed>24357662</pubmed></ref><br />
<br />
This review describes both human and animal studies of Notch signalling during pregnancy. It explains research of Notch signalling at the human blastocyst-maternal interface, and that Notch signalling has been observed in both the maternal endometrium and the blastocyst. Furthermore, Notch signalling is also important for the processes of implantation and placentation. Overall, the review summarises findings of Notch signalling in endometrial-trophectoderm interactions during the implantation, regulation of extravillous trophoblast invasion and spiral artery remodelling in the decidua, and angiogenesis in the placenta, as well as how abnormal Notch signalling is related with impaired placentation and pre-eclampsia.<br />
|}<br />
<br><br />
<br />
===Glossary===<br />
{| class="pretty table"<br />
|-<br />
| '''AER'''<br />
| 'Apical Ectodermal Ridge' is a structure that forms from the ectodermal cells at the distal end of each limb bud. The AER acts as a major signalling centre in order to ensure proper limb development.<br />
|-<br />
| '''Apoptosis'''<br />
| Programmed cell death which occurs in the development of many systems.<br />
|-<br />
| '''Calcification'''<br />
| The accumulation of calcium salts in body tissue. It normally occurs in the formation of bone, but abnormally calcium can be deposited in soft tissue causing it to harden.<br />
|-<br />
| '''Cardiogenic'''<br />
| From cardiogenesis - meaning formation of the heart.<br />
|-<br />
| '''Cardiomyocyte'''<br />
| The muscle cells (myocytes) that make up the cardiac muscle<br />
|-<br />
| '''Congenital'''<br />
| (Of a disease or physical abnormality) present from birth.<br />
|-<br />
| '''Craniofacial'''<br />
| Meaning relating to the cranium and the face.<br />
|-<br />
| '''Cyclin D1'''<br />
| A protein required for progression through the G1 phase of the cell cycle. Read more about it [https://en.wikipedia.org/wiki/Cyclin_D1 here], or see information on its encoding gene here: [http://omim.org/entry/168461 OMIM168461].<br />
|-<br />
| '''Endocardial'''<br />
| From endocardium - meaning the thin, smooth membrane which lines the inside of the chambers of the heart and forms the surface of the valves.<br />
|-<br />
| '''Endocrine'''<br />
| As in the endocrine system, refers to glands that secrete hormones or other substances directly into the blood.<br />
|-<br />
| '''Epithelium'''<br />
| The thin tissue that forms the outer layer of a body's surface and also lines the alimentary canal and other hollow structures.<br />
|-<br />
| '''Gastrulation'''<br />
| Describes the formative process of the formation of the trilaminar embryo containing the three germ layers.<br />
|-<br />
| '''Gliogenesis'''<br />
| The formation and development of glial cells (astrocytes, oligodendrocytes, Schwann cells, microglia).<br />
|-<br />
| '''Haematopoietic'''<br />
| From haematopoiesis - meaning the formation of blood cellular components<br />
|-<br />
| '''Haploinsufficiency'''<br />
| When a diploid organism has only a single functional copy of a gene (with the other copy inactivated by mutation), and so the total level of a gene product (a particular protein) produced by the cell is about half of the normal level.<br />
|-<br />
| '''Homeostasis'''<br />
| The ability to maintain a constant internal environment in response to environmental changes.<br />
|-<br />
| '''Ligand'''<br />
| A molecule that binds to a specific binding site on a protein (receptor).<br />
|-<br />
| '''Mef2C promoters'''<br />
| Myocyte-specific enhancer factor 2C is a transcription factor in the Mef2 family that is encoded by the gene ''MEF2C'' in humans ([https://omim.org/entry/600662 OMIM 600662]). This gene is involved in cardiac morphogenesis and myogenesis, as well as vascular development. It is thought to also possibly play a role in neurogenesis.<br />
|-<br />
| '''Mesenchymal'''<br />
| From mesenchyme - meaning a loosely organised, mainly mesodermal embryonic tissue which develops into connective and skeletal tissues, including blood and lymph.<br />
|-<br />
| '''Morphogenesis'''<br />
| Refers to the origin and development of morphological characteristics.<br />
|-<br />
| '''Myogenic'''<br />
| From myogenesis - meaning formation of muscle.<br />
|-<br />
| '''Myogenin'''<br />
| Also known as myogenic factor 4, this is a muscle-specific basic-helix-loop-helix transcription factor involved in the coordination of skeletal muscle development or myogenesis and repair.<br />
|-<br />
| '''Neural Crest'''<br />
| In vertebrate embryos, this is a transient structure that gives rise to most of the peripheral nervous system and to a number of non-neural cell types such as the smooth muscle cells of the cardiovascular system. <br />
|-<br />
| '''Neurogenic'''<br />
| From neurogenesis - meaning the formation of nervous tissue.<br />
|-<br />
| '''Neurulation'''<br />
| The folding process in vertebrate embryos whereby the neural plate transforms into the neural tube.<br />
|-<br />
| '''NICD'''<br />
| Notch intracellular domain<br />
|-<br />
| '''Oncogenic'''<br />
| From oncogenesis, also known as tumorigenesis or carcinogenesis - meaning the formation of a cancer, whereby normal cells are transformed into cancer cells.<br />
|-<br />
| '''Paracrine'''<br />
| A hormone that exerts an effect only in the vicinity of the gland secreting it.<br />
|-<br />
| '''Protease'''<br />
| An enzyme which breaks down proteins and peptides.<br />
|-<br />
| '''Runx2'''<br />
| Runt-related transcription factor 2 is a protein that in humans is encoded by the ''RUNX2'' gene ([http://omim.org/entry/600211 OMIM600211]). RUNX2 is an important transcription factor associated with osteoblast (bone substance-secreting cells) differentiation.<br />
|-<br />
| '''Stromal cells'''<br />
| The connective tissue cells of any organ. They support the function of the parenchymal cells of that organ. Fibroblasts and pericytes are among the most common types of stromal cells.<br />
|-<br />
|}<br />
<br />
====Further Glossary Links====<br />
[[A|A]] | [[B|B]] | [[C|C]] | [[D|D]] | [[E|E]] | [[F|F]] | [[G|G]] | [[H|H]] | [[I|I]] | [[J|J]] | [[K|K]] | [[L|L]] | [[M|M]] | [[N|N]] | [[O|O]] | [[P|P]] | [[Q|Q]] | [[R|R]] | [[S|S]] | [[T|T]] | [[U|U]] | [[V|V]] | [[W|W]] | [[X|X]] | [[Y|Y]] | [[Z|Z]] | [[Numbers|#]]<br />
<br />
===References===<br />
<references/></div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=2016_Group_Project_2&diff=255184
2016 Group Project 2
2016-10-27T08:27:55Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016header}}<br />
{{Group Assessment Criteria table}}<br />
<!-- Do not delete the above template from the Group project page. --><br />
=The Notch Signalling Pathway=<br />
===Introduction===<br />
The Notch signalling pathway is the most prevalent form of intracellular communication in multicellular organisms. It is a critical pathway for cell differentiation, proliferation, and apoptosis. It is involved in embryonic organ development through the regulation of cell-cell signalling; specifically lateral inhibition, formation of boundaries, and cell lineage assignation.<ref name="The Developing Human">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2015). The developing human: clinically oriented embryology (10th ed.). Philadelphia: Saunders.</ref><ref name="PMID10075488">As reviewed by <pubmed>10075488</pubmed></ref> This pathway is also actively involved in adjacent cell communication, developmental process such as adult homeostasis, and stem cell maintenance. Since this pathway is an intricate and crucial aspect of an organism's development and cell signalling, a mutation in the functional components of this pathway can cause a myriad of diseases such as congenital disorders, cancers, strokes, Alagille syndrome, and leukoencephalopathy.<ref name="PMID19255248">As reviewed by <pubmed>19255248</pubmed></ref> The process of Notch signalling primarily utilises a ligand-receptor interaction to release protein fragments at the cellular membrane, which then provide signals to the internal environment of the cell and to adjacent cells. In mammals, the Notch signalling pathway is comprised of four receptors (Notch 1-4) which interact with Delta or Jagged ligands to bring about the activation of this pathway. Homologous Notch genes have been identified in other animals, such as ''Drosophila melanogaster'' (fruit fly) and ''Danio rerio'' (zebrafish).<br />
<br><br />
<br />
<big>What will you find on this wiki page?</big><br />
<br />
This page is designed to provide an overview of such features of the Notch signalling pathway, but is in no way a complete resource for all Notch-related information (especially since this signalling pathway has such a wide array of activities in many organisms and the scientific understanding of it is continuously updating!). By reading this page you should come to a better understanding of Notch in regards to: general molecular mechanisms; embryonic development by systems; examples of animal development; abnormalities and disease; current and potential future research; as well as a couple of links to interesting articles for those who want to read more. There is a [[#Glossary| Glossary]] at the bottom of the page for better understanding of scientific terms used throughout this page, and readers are encouraged to 'expand' any collapsed information on the page to optimise their experience in reading about Notch. <br />
<br><br><br />
<div align="center"><html5media width="560" height="315">https://www.youtube.com/embed/axkDX0XZyN0</html5media></div><br />
<br><br />
<br />
===History===<br />
{| class="pretty table"<br />
|-bgcolor="FAF5FF" <br />
| 1914<br />
| First description of a "notch" defect (loss of tissue in the wing) in ''Drosophila'' by John S. Dexter, giving the gene its name<ref>Dexter, J. (1914). The Analysis of a Case of Continuous Variation in Drosophila by a Study of Its Linkage Relations. ''The American Naturalist'', 48(576), 712-758. Retrieved from http://www.jstor.org/stable/2455888</ref><br />
|-<br />
| 1917<br />
| First allele of ''Notch'' is identified by Thomas Hunt Morgan<ref>Morgan, T. H. (1917). The theory of the gene. ''The American Naturalist'', 51(609), 513-544.</ref><br />
|-bgcolor="FAF5FF" <br />
|-<br />
| 1930s<br />
| Donald F. Poulson conducts research into the involvement of ''Notch'' in development.<ref><pubmed>16588136</pubmed></ref> <br />
|-<br />
| 1958<br />
| An investigation by W.J. Welshons confirmed that the locus of Notch is contained within the 3C7 band of the X chromosome.<ref><pubmed>13635554</pubmed></ref><br />
|-bgcolor="FAF5FF" <br />
|-<br />
| 1983<br />
| DNA sequences belonging to the Notch locus cloned and determined that RNA is required for the function of the wild type Notch. Further insight developed into the function of Notch and its role in differentiation and regeneration.<ref><pubmed>6403942</pubmed></ref><br />
|-<br />
| 1986<br />
| The molecular analysis and sequence of the Notch locus was determined by Michael W. Young and his team. A relationship was identified between the protein encoded by the major Notch transcript and mammalian clotting and growth factors.<ref><pubmed>3097517</pubmed></ref><br />
|-bgcolor="FAF5FF" <br />
|-<br />
| 1989<br />
| Neurogenic loci "Delta" and "Mastermind" identified and research conducted to search for genes which may have an interaction with the Notch protein. It was confirmed that mutations in these loci will affect neurogenesis.<ref><pubmed>2338245</pubmed></ref><br />
|-<br />
| 2012<br />
| The Notch ligand Jag1 was expressed in PA6 cells and showed demonstrated that the ability for the cells to differentiate was interrupted by the Notch signalling inhibition pathway. <ref><pubmed>22558462</pubmed></ref><br />
|}<br />
<br />
===Overview of Molecular Mechanisms===<br />
Mammals possess a total of four ''Notch'' genes, with five genes for encoding the associated ligands, Delta-like and Jagged. The ''Notch'' genes each code for a single transmembrane receptor. Extracellularly, it contains epidermal growth factor (EGF)-like repeats for ligand interaction and Lin-12-Notch (LN) repeats for regulating the interactions between the extracellular and intracellular regions. Intracellularly, Notch has seven ankyrin (ANK) repeats and a transactivation domain (TAD), as well as a proline, glutamine, serine, threonine-rich (PEST) domain for degradation of Notch.<br />
<br><br><br />
[[File:Notch structure cartoon.jpg|thumb|700px|center|'''The structure of the Notch receptor.'''<ref name="PMID19255248"/> Extracellularly there are epidermal growth factor (EGF)-like repeats and Lin-12-Notch repeats (LNRs). The Notch intracellular domain (NICD) is made up of a rRBP-Jkappa-associated module (RAM) domain, ankyrin (ANK) repeats, and a proline, glutamine, serine, threonine-rich (PEST) domain. There are three sites for cleavage by enzymes: S1, S2, and S3/S4.]]<br />
<br />
====Canonical pathway====<br />
[[File:Overview of Notch signalling.png|thumb|500px|'''Summary of canonical Notch signalling.''' The interaction between Delta-like or Serrate ligands (DSL) and the Notch receptor on an adjacent cell initiates proteolytic cleavage of Notch and the release of the Notch intracellular domain (NICD). The NICD is then transported to the nucleus where it can induce transcription of Notch target genes by binding to specific proteins (MAM, CSL).<ref><pubmed>27404588</pubmed></ref>]]<br />
The canonical Notch pathway is unique in that it involves direct interaction between adjacent cells, as opposed to paracrine signalling, because both the Notch ligands and Notch receptors are transmembrane proteins found in the cell membrane. Furthermore, the lack of a secondary messenger or amplification process means that the Notch pathway has limited opportunities for regulation and must therefore be tightly controlled. Depending on its developmental and cellular context, activation or inhibition of the pathway can result in a variety of cellular responses, including cell death, proliferation, or differentiation.<ref name="Introduction to Notch Signalling">Yamamoto, S., Schulze, K.L. & Bellen, H.J. (2014). Introduction to Notch Signalling. ''Notch Signaling: Methods and Protocols''. Methods in Molecular Biology: 1187</ref><br />
<br><br><br />
Four Notch proteins are involved in the canonical pathway. NOTCH1 to NOTCH4 are single transmembrane receptors and can interact with a variety of ligands, including NOTCH ligands (e.g. Delta ligands) and Serrate ligands. There are three Delta ligands (Dll1, Dll3, and Dll4) and two Serrate ligands (Jagged1 and Jagged2) present in mammals.<ref name="Introduction to Notch Signalling"/> The binding between the Notch receptor and the ligand on the adjacent cell induces the release of the Notch intracellular domain (NICD) via a sequence of proteolytic reactions.<ref name="The Developing Human"/> Cell-cell interaction is therefore critical in the process of triggering Notch signalling.<br />
<br><br><br />
The interaction on the cell surface between Notch and its ligand on an adjacent cell causes the extracellular metalloprotease site (S2 site) to be exposed. The S2 site is then cleaved by transmembrane proteases belonging to the a disintegrin and metalloproteinase/tumour necrosis factor α converting enzyme (ADAM/TACE) family. The remaining Notch fragment subsequently undergoes two more intramembranous cleavages at the S3/S4 sites by the γ-secretase complex. Finally, the NICD is released and enters the nucleus to interact with CSL (CBF1, Suppressor of Hairless, Lag-1) and Mastermind-like proteins (MAMLs). CSL is a DNA-binding protein that acts as a transcription factor by forming repressor or activator complexes; in the absence of the NCID, CSL is bound to corepressor proteins (CoR) that prevent transcription of Notch target genes. MAMLs are transcriptional co-activators that are required for transcription of the target genes, hence they are involved in the regulation of the pathway.<ref name=PMID10075488/><ref name="Introduction to Notch Signalling"/> To stop signalling, the NICD is phosphorylated by kinases and ubiquitinated by E3 ubiquitin ligases, which results in proteasome mediated degradation and subsequent termination of the signal.<ref name="Introduction to Notch Signalling"/><br />
<br><br><br />
<br />
====Non-canonical pathway====<br />
Immense research has been carried out on the canonical Notch pathway and its members are well known. While canonical notch ligands control most of the known Notch signalling, a group of structurally distinct non-canonical ligands exist which activate Notch and its pleiotropic effects. Notch can non-canonically carry out its functions by post-translationally targeting Wnt/β-catenin signalling. This type of signalling is CSL-independent and can also work independently of ligands. Some genes are affected by the non-canonical Notch signalling, however their mediators in most cases are unknown. Notch binds and titrates levels of active β-catenin. Therefore, active β-catenin activity may serve as a useful readout for non-canonical Notch signals.<ref name="PMID22397947">As reviewed by <pubmed>22397947</pubmed></ref> <br />
<br />
Recent research has shown that Notch signalling plays crucial roles for cellular differentiation during development through γ-secretase-dependent intramembrane proteolysis followed by transcription of target genes. Hayashi et al. (2016) uncovered a ligand-dependent but γ-secretase-independent, non-canonical Notch signalling involved in presynaptic protein expression in postmitotic neurons.<ref name="PMID27040987"><pubmed>27040987</pubmed></ref><br />
<br><br><br />
<br />
====Transcriptional regulation of Notch signalling====<br />
A number of genes have been found to act as modulators of Notch signalling by modifying the ability of Notch to interact with its ligands. These include proteins acting extracellularly (Fringe, Brainiac, Egghead, Scabrous, Wingless), proteins acting at the cell membrane (Big brain), proteins acting intracellularly (Numb, Sanpodo, Disabled, Deltex, Dishevelled), and proteins acting within the nucleus (Hairless, EMB-5, Strawberry notch).<ref name="PMID9892565">As reviewed by <pubmed>9892565</pubmed></ref><br />
<br />
In ''Drosophila melanogaster'', it has been seen that ''fringe'' is able to affect the ability of Notch to be activated by the Serrate and Delta ligands. Specifically in the ''Drosophila'' wing, it was observed that Serrate did not interact with Notch in specific areas due to the action of ''fringe''<ref><pubmed>9247339</pubmed></ref>. Fringe is not required for initial Notch signalling, but is thought to be important for signalling processes when Notch activation occurs along the borders between distinct cell populations. Research suggests that Fringe specifically affects the binding between Notch and its ligands, rather than an activation step separate or subsequent to ligand binding. The ''brainiac'' and ''egghead'' genes are thought to either influence the production of a Notch ligand or act as substitute ligands themselves.<ref name="PMID9892565"/><br />
<br><br><br />
<br />
====Examples of Proteins Involved in Interaction with the Notch Intracellular Domain <small>(adapted from Table 3<ref name="PMID21828089"/>)</small>====<br />
{| class="pretty table"<br />
|-bgcolor="A3BFB1" <br />
| '''Protein'''<br />
| '''Interaction with NICD'''<br />
|-bgcolor="F5FFFA"<br />
| Adenamatous polyposis coli (Apc)<br />
| Controls Notch trafficking<br />
|-<br />
| Cyclin-dependant kinase 8 (CDK8)<br />
| Phosphorylates NICD to make it a substrate for ubiquitylation and degradation<br />
|-bgcolor="F5FFFA"<br />
| CBF1, Su(H) and LAG-1/Recombination signal binding protein for immunoglobulin kappa J region (CSL/RBP-J)<br />
| Main canonical transcriptional co-factor for NICD<br />
|-<br />
| Cyclin C (CycC)<br />
| Targets NICD for phosphorylation to make it a substrate for ubiquitylation and degradation<br />
|-bgcolor="F5FFFA"<br />
| Dishevelled (Dsh/Dvl)<br />
| Controls ligand-independent Notch trafficking; inhibits canonical Notch signalling<br />
|-<br />
| Deltex-1-4 (Dtx1-4)<br />
| Controls Notch ubiquitylation, processing, and internalisation<br />
|-bgcolor="F5FFFA"<br />
| Itchy, E3 ubiquitin protein ligase (Itch)<br />
| Promotes ubiquitylation of NICD<br />
|-<br />
| Mastermind-like 1/2 (Maml1/2)<br />
| Co-activator for NICD/CSL<br />
|-bgcolor="F5FFFA"<br />
| Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-ϰb)<br />
| NICD blocks NF-ϰb transcription of NF-ϰb target genes through binding to p50/cRel<br>NICD enhances NF-ϰb transcription of target genes by retaining NF-ϰb in the nucleus<br />
|-<br />
| Numb homolog (Numb)<br />
| Suppresses Notch signaling by recruiting E3 ubiquitin ligases to ubiquitylate Notch<br>Controls Notch trafficking during asymmetric cell division<br />
|-bgcolor="F5FFFA"<br />
| Smad family members (SMAD)<br />
| Smads enhance Notch signalling; Notch fine-tunes signalling through Smads<br />
|}<br />
<br><br />
<br />
===Roles in Embryonic Development===<br />
The phylogenetically conserved Notch signalling pathway plays a crucial role in the development of multiple organ systems, and is a major regulator of stem cell fate. It is responsible for the regulation of the transcription of a number of signalling molecules, such as ''MyoD'', ''Mash1'' and ''GATA2'', which are genes controlling the fate of myogenic, neurogenic and haematopoietic stem cells, respectively. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> The following subsections will further elucidate the vital roles of Notch signalling during normal embryonic development. If you would like to better understand human embryonic development before reading this section, [https://embryology.med.unsw.edu.au/embryology/index.php/Embryonic_Development| this page] serves as a great resource. <br />
<br><br><br />
<br />
====Cardiovascular====<br />
<br />
If you would like to generally learn about and become familiar with cardiac development in the embryo before reading this section, click [https://embryology.med.unsw.edu.au/embryology/index.php/ANAT2341_Lab_11_-_Heart here]!<br />
<br />
'''Cardiomyocyte Specification and Differentiation'''<br />
<br />
Expression during the appropriate window of the timeline of embryogenesis of Notch receptors, ligands and downstream effector molecules elucidates a role for the Notch pathway in the earliest stages of cardiac development. It has been found to restrict the expression of specific cardiogenic genes in a spatiotemporal manner and regulate cardiac field specification as early as during gastrulation. <ref name=PMID19580804><pubmed>19580804</pubmed></ref> Interestingly, Notch has been found to play both suppressive and promoting roles in cardiogenesis.<br />
<br />
For example, it has been shown that Notch suppresses cardiomyocyte cell fate specification during early cardiogenesis. This has been demonstrated through studies such as that carried out by Rones and colleagues (2000), which used activation and inhibition of Notch signaling in Xenopus. <ref name=PMID10934030><pubmed>10934030</pubmed></ref><br />
<br />
On the other hand, studies such as that by Boni et al. (2008) have found that Notch signalling may also promote myogenesis from cardiac progenitor cells. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> Cardiogenesis has also been promoted by downregulating Notch-1 activity in stem cells of embryos (Nemir et al., 2006).<ref name=PMID16690879><pubmed>16690879</pubmed></ref><br />
<br />
Despite the understanding that Notch signalling is crucial to embryonic myogenesis, the exact molecular mechanism remains elusive. Research by Buas and colleagues (2010) has explored such mechanisms by studying the Notch target, Hey1, which is known to suppress myogenic differentiation. They concluded that this inhibitory function of Hey1 is primarily mediated through binding near to myogenin and Mef2C promoters, which leads to cessation of target gene expression. <ref name=PMID19917614><pubmed>19917614</pubmed></ref><br />
<br />
[[File:Notch CVS simple diagram.png|thumb|500px|right|alt=Simplified Scheme of the Roles of Notch in Cardiac Development|'''Simplified Scheme of the Roles of Notch in Cardiac Development.''' Notch has been found to restrict the expression of specific cardiogenic genes in a spatiotemporal manner and regulate cardiac field specification early in development. Further after cardiac differentiation, Notch influences development of the AVC (atrioventricular canal), cardiac valves, ventricular trabeculae and the cardiac outflow tract. (This student-drawn image is based upon Figure 2 in the 2014 review by Zhou and Liu: [https://www.ncbi.nlm.nih.gov/pubmed/24345875 ''Role of Notch signaling in the mammalian heart.'']<ref name=PMID24345875><pubmed>24345875</pubmed></ref>)]]<br />
<br />
'''Development of the Atrioventricular Canal'''<br />
<br />
A study by Rutenberg et al. (2006) and another by Kokubo et al. (2007) implicate a role for Notch signaling in the region between the atria and the ventricles of the heart (the atrioventricular canal, or AVC).<ref name=PMID17021042><pubmed>17021042</pubmed></ref> <ref name=PMID17259303><pubmed>17259303</pubmed></ref> They used chicken and mouse models, respectively, to show that other signalling factors, ''Bmp2'' and ''Tbx2'', are restricted to the AVC region by Notch signalling during development. <br />
<br />
Furthermore, Watanabe and colleagues (2006) showed that deletion of Notch targets increases ''Bmp2'' expression and expansion of the AVC tissue, however other, non-Notch restrictive factors involved in AVC development are likely to exist.<ref name=PMID16554359><pubmed>16554359</pubmed></ref> <br />
<br />
'''Heart Valve Development'''<br />
<br />
In order for the heart valve to properly form in the embryo, endocardial to mesenchymal transformation (EMT) must occur. The Notch pathway, alongside Wnt and Bmp, has been found to regulate the process of EMT, defects in which can lead to congenital heart valve disease. Interestingly, Timmerman and colleagues (2004) demonstrated that this role of Notch may also promote oncogenic transformation. This team also showed that embryos exhibited abortive endocardial EMT if they were deficient in Notch signalling components in vivo and in vitro. <ref name=PMID14701881><pubmed>14701881</pubmed></ref> <br />
<br />
A more recent paper by Wang et al. (2013) further explored the underlying signalling processes and interrelationships of molecules that impact EMT. They found that Jagged1-Notch1 signalling in cells of the endocardium potentiates expression of Wnt4, which in turn carries out paracrine action on adjacent AVC tissue to upregulate Bmp2 expression and thus signal EMT. <ref name=PMID23560082><pubmed>23560082</pubmed></ref><br />
<br />
'''Trabeculation'''<br />
<br />
Trabeculation is the initial process of ventricular chamber development that forms a series of cardiomyocyte projections within the lumens of the ventricles of the heart (called trabeculae). Grego-Bessa and colleagues (2007) addressed the roles Notch plays in trabeculation through ''RBPJk'' (the gene product of which interacts with Notch) and ''Notch1'' gene manipulation. Mutants of these two genes showed perturbed expression and signalling of ''EphrinB2'', ''NRG1'' and ''BMP10'', alongside reduced proliferation of myocardiocytes. This research ultimately suggested that ''EphrinB2'' is a direct target of Notch in the endocardium that simultaneously requires the Notch-dependent action of BMP10 and NRG1 in order for ventricular myocardium proliferation and differentiation to occur normally. <ref name=PMID17336907><pubmed>17336907</pubmed></ref> Furthermore, the important process of trabeculation has recently been shown to be controlled by sequential Notch activation by an investigation by D’Amato et al. (2015). <ref name=PMID26641715><pubmed>26641715</pubmed></ref><br />
<br />
'''Development of the Outflow Tract'''<br />
<br />
About one third of congenital heart defects include malformations in the outflow tract which include the aorta, pulmonary arteries, aortic arch and ductus arteriosus. During cardiogenesis, neural crest cells interact with second heart field myocardium and endocardial mesenchyme. <ref><pubmed>20201902</pubmed></ref> <br />
Studies involving neurogenesis demonstrated the sensitivity of Notch signaling to temporal and spatial cues and showed the early Notch signaling initially controls the number of cells with a neurogenic fate and later dictates the lineage decision of neural versus glial cell fate. <ref><pubmed>16429119</pubmed></ref><br />
Neural crest precursors for ideal patterning of the outflow tract are required in the Notch signaling pathway. The use of a dominant negative form of a master mind like protein (MAML) which has shown to be a pan Notch inhibitor in neural crest cells inactivates Notch signaling. This results in congenital heart defects like pulmonary artery stenosis and aortic arch patterning defects associated with defects in smooth muscle formation. <ref><pubmed> 17273555 </pubmed></ref><br />
Part of the phenotype in defective neural crest cells is attributed to loss of Notch2 signalling as Notch2 inactivation in these cells produces small caliber aortas and pulmonary arteries because of defects in smooth muscle. <ref><pubmed> 18330927 </pubmed></ref><br />
Jagged1 is the ligand involved which signals to Notch on neural crest cell surfaces to induce vascular smooth muscle cell differentiation. <ref><pubmed> 18245384 </pubmed></ref><br />
Mutations in both JAGGED1 and NOTCH2 genes have been known to cause Alagille syndrome, further substantiating the importance of this pathway in proper formation of the outflow tract. <ref><pubmed> 16575836 </pubmed></ref><br />
<br />
Another study by Garg stresses the importance of Notch signaling in the outflow tract region. NOTCH1 mutations were seen in patients with aortic stenosis. Aortic stenosis results from the calcification of the aortic valve and is quite common in adults. However, in children, this may result in failure of the left ventricle to develop properly. NOTCH1 haploinsufficiency is also linked to early calcification and bicuspid aortic valve disease. This could be due to an early induction of Runx2 through the HRT genes.<br />
<ref><pubmed> 16025100 </pubmed></ref><br />
<br />
<br><br><br />
<br />
====Central Nervous System====<br />
<br />
If you would like to generally learn about and become familiar with neural development in the embryo before reading this section, click [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Neural_Development here]!<br />
<br />
[[File:Notch CNS simple diagram.png|thumb|450px|right|alt=Simplified Diagram of Roles of Notch in Neuronal Differentiation|'''Simplified Diagram of Roles of Notch in Neuronal Differentiation'''. Notch influences the differentiation of embryonic stem cells into neural cells via signalling with RBP (recombining binding protein), cyclin D1 and Hes1. (This student-drawn image is based upon Figure 1 from Chuang, Tung and Lin's 2015 review: [https://www.ncbi.nlm.nih.gov/pubmed/25815127 ''Neural differentiation from embryonic stem cells in vitro: An overview of the signaling pathways'']<ref name="PMID25815127"><pubmed>25815127</pubmed></ref>)]]<br />
'''Early Neural Differentiation'''<br />
<br />
Notch plays a major role in promoting neural commitment of cells. Lowell and colleagues (2011) used genetic manipulation to discover that the phenotype of stem cells is not affected by constitutively activated Notch in mouse embryonic stem cells (mESCs), however, interfering with Notch signalling -for example by pharmacological means- did impede neural fate determination. This role required Notch signalling via fibroblast growth factor (FGF) receptors. Furthermore, the conservation of the Notch signalling pathway within pluripotent stem cells is implied due to the existence of Notch ligands in stromal cells in human embryonic stem cells (hESCs) that induce neural differentiation. <ref name=PMID16594731><pubmed>16594731</pubmed></ref><br />
<br />
Das and colleagues (2010) manipulated Notch protein levels during specific stages of neural differentiation and found that if Notch signalling pathways were activated during day 3 of neural development for 6 hours, cell proliferation was dramatically enhanced. This was attributed to the induction by Notch of cyclin D1 expression. Without Notch signalling during neural development, there was reduced cyclin D1 levels. Manipulation of mESCs to express a dominant negative form of cyclin D1 resulted in abrogation of cell proliferation stimulated by Notch. Overall these results imply a temporally-specific role for Notch in CNS development, and that it requires cyclin D1 as a signalling molecule.<ref name=PMID20887720><pubmed>20887720</pubmed></ref><br />
<br />
Hes1 has also been shown to play a Notch-mediated role in neural progenitor maintenance, which is essential for proper development since cells need to proliferate only during specific periods in the embryo for the correct number, cell type and function to result. Shimojo, Ohtsuka and Kageyama (2008) used real time imaging in mice to show that Notch induces oscillatory expression of ''Hes1'' and other Notch target genes to maintain the complex temporal organisation of events in neural development. They concluded that further research could elucidate more about Hes1 oscillations in regards to neural progenitor maintenance, proliferation and differentiation <ref name=PMID18400163><pubmed>18400163</pubmed></ref>.<br />
<br />
Lastly, as well as influencing neural progenitor differentiation, it has been found that Notch also impacts the development and maintenance of polarised neural structures in the embryo. This was concluded from a knockout study in mice that elucidated a role for RBP (recombining binding protein), downstream of Notch, in modulating neural differentiation and maintaining rosette structure (an experimental ''in vitro'' correlate used for neural tube development) <ref name=PMID23675446><pubmed>23675446</pubmed></ref>. The researchers concluded that RBP knockouts lacked canonical Notch signalling and as a result showed multiple neurulation defects.<br />
<br><br><br />
<br />
====Other Systems====<br />
<br />
As aforementioned, Notch plays a wide array of roles in embryonic development, the follow table summarises these roles by each organ system:<br />
<br />
<big>Summary Table of Examples of Notch Signalling in Developmental Processes</big> <small>(adapted from Table 1<ref name="PMID21828089">As reviewed by <pubmed>21828089</pubmed></ref>)</small><br />
{| class="pretty table"<br />
|-bgcolor="CEDFF2"<br />
| '''Organ/Tissue'''<br />
| '''Processes regulated by Notch'''<br />
|-bgcolor="F5FAFF" <br />
| Brain<br />
| Controls the balance between gliogenesis and neurogenesis; stem cell maintenance<ref><pubmed>21262462</pubmed></ref><ref>As reviewed by <pubmed>20816397</pubmed></ref>; organisation and maintenance of polarity during early development<ref name="PMID23675446"/><br />
|-<br />
| Craniofacial structures<br />
| Palate morphogenesis: loss of Notch signalling results in cleft palate, fusion of the tongue with the palatal shelves, and other craniofacial defects; also involved in tooth development<br />
|-bgcolor="F5FAFF"<br />
| Ear<br />
| Defines the presumptive sensory epithelium; determines hair cell and supporting cell fates<br />
|-<br />
| Esophagus<br />
| Regulates esophageal epithelial homeostasis<br />
|-bgcolor="F5FAFF"<br />
| Heart<br />
| Cardiac patterning, cardiomyocyte differentiation, valve development, ventricular trabeculation, outflow tract development<br />
|-<br />
| Intestine<br />
| Controls proliferation and differentiation, including absorptive vs. secretory cell fates<br />
|-bgcolor="F5FAFF"<br />
| Limbs<br />
| Apical ectodermal ridge (AER) formation and digit morphogenesis, especially regulation of apoptosis<br />
|-<br />
| Lungs<br />
| Lateral inhibition between tracheal cells prevents extra cells from assuming the lead position during tracheal branching morphogenesis<br />
|-bgcolor="F5FAFF"<br />
| Neural crest<br />
| Controls patterning of neural crest precursors for the outflow tract region of the heart; regulates the transition from Schwann cell precursor to Schwann cell, controls Schwann cell proliferation and inhibits myelination; controls melanocyte stem cell maintenance<br />
|-<br />
| Pancreas<br />
| Specifies endocrine cell differentiation through lateral inhibition: endocrine lineage cells inhibit endocrine differentiation of their neighboring cells; maintains pancreatic endocrine precursor cells, inhibits terminal acinar cell differentiation; controls pancreatic epithelium branching and bud size<br />
|-bgcolor="F5FAFF"<br />
| Skin<br />
| Regulates cell adhesion, control of proliferation, hair follicle or feather papillae differentiation and homeostasis<br />
|-<br />
| Thyroid<br />
| Regulates the numbers of thyrocyte and C-cell progenitors and regulates differentiation and endocrine function of thyrocytes and C-cells<ref><pubmed>21364918</pubmed></ref><br />
|-bgcolor="F5FAFF"<br />
| Vasculature<br />
| Regulates arteriovenous specification and differentiation in endothelial cells and vascular smooth muscle cells; regulates blood vessel sprouting and branching<br />
|}<br />
<br />
====Quiz Your Notch-Knowledge on Embryonic Development!====<br />
<br />
<quiz display=simple><br />
<br />
{ In the development of which organ does Notch exert lateral inhibition to differentiate endocrine cells?<br />
|type="()"}<br />
- &nbsp; The heart<br />
- &nbsp; The central nervous system<br />
- &nbsp; The skin<br />
+ &nbsp; The pancreas<br />
|| Remember, Notch signals endocrine lineage cells of the developing pancreas to inhibit endocrine differentiation of their neighbouring cells, known as lateral inhibition. Notch plays various roles in the heart, central nervous system and skin, but not in this way. <br />
</quiz><br />
<br><br />
<br />
===Roles in Animal Development===<br />
The Notch signalling pathway doesn't just play a significant role in human development, but also affects events such as neurogenesis and myogenesis in some animals (thus why these animals are often used as models for human development in research!). Read below for information on some of these roles for Notch.<br />
<br><br><br />
<br />
[[File:Notch animals.png|thumb|450px|right|alt=Animals Whose Developmental Processes are Affected by Notch.|'''Animals Whose Developmental Processes are Affected by Notch.''' This is a simplified representation of a few examples of the animals (Drosophila flies<ref name=PMID21447553><pubmed>21447553</pubmed></ref>, C. elegans<ref name=PMID18599512><pubmed>18599512</pubmed></ref>, and the zebrafish<ref><pubmed>23840804</pubmed></ref>) in which development is influenced by the Notch signalling pathway, and their scientific names.]]<br />
<br />
====''Drosophila melanogaster''====<br />
<br />
'''(The Fly)'''<br />
<br />
Unlike the four Notch paralogs in humans, only one Notch homolog is present in ''Drosophila''.<ref name="Introduction to Notch Signalling"/><br />
<br />
Both canonical and non-canonical Notch signalling are involved in the structural and physiological responses and functional plasticity of olfactory receptor neurons in reaction to prolonged odour exposure.<ref><pubmed>26986723</pubmed></ref><ref><pubmed>26011623</pubmed></ref> Research has also shown that Notch is crucial for the formation of longitudinal connections in the Drosophila CNS. Kuzina, Song, and Giniger (2011) created temperature-sensitive mutations of Notch genes that prevented the development of mature longitudinal axon tracts. Additionally, it was found that the Notch phenotype appears at the earliest stages of the development of longitudinal connections in the CNS by observing early stage 13 embryos.<ref name=PMID21447553><pubmed>21447553</pubmed></ref><br />
<br><br><br />
<br />
====''Caenorhabditis elegans''====<br />
<br />
'''(The Worm)'''<br />
<br />
The Notch pathway in ''C. elegans'' occurs throughout development in populations of equipotent cells for neuronal function in postmitotic differentiated neurons. In these postmitotic neurons, there is a specialised post-embryonic development stage knows as 'dauer'. The Notch pathway is activated when cell signalling downstream of the developmental decision enter dauer. The Notch receptor glp-1 and the ligand lag-2 are expressed in the dauer stage and aid in maintaining this stage. Another Notch receptor, lin-12, functions upstream of insulin signalling components to promote conditions for growth and enhance dauer recovery. <ref name=PMID18599512><pubmed>18599512</pubmed></ref><br />
<br><br><br />
<br />
====''Danio rerio''====<br />
<br />
'''(The Zebrafish)'''<br />
<br />
The expression of Notch in the myogenic region and apical ectodermal ridge (AER) of the developing zebrafish fin is similar to what has been observed in developing chicken and mouse limbs, which shows how highly conserved the role of Notch signalling is in the development of appendages in vertebrates. During zebrafish embryogenesis, the timing and positioning of fin formation are dependent on Notch signalling. Notch is also involved in the actual processes of fin formation, such as AER signalling, chondrogenic differentiation, and myogenesis. In zebrafish embryos with defective Notch signalling, it was observed that the skeletal muscle fibres were thin and fragmented and the structure of the sarcomeres was significantly compromised. <ref name="PMID23840804"><pubmed>23840804</pubmed></ref><br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Expand this for an image from this research study</big><br />
|-<br />
|[[File:Abnormal pectoral fins are formed in Notch signalling disrupted larvae.jpg|thumb|450px|right|alt=Abnormal pectoral fins are formed in Notch signalling disrupted larvae|'''Abnormal pectoral fins are formed in Notch signalling disrupted larvae.''' (A–F) Live pictures of 5 dpf larvae. (A’) A pectoral fin from a sibling embryo showing the cartilaginous endoskeletal disc with individualized cells surrounded by thin matrix deposits, the fin fold and the chleitrum (n = 17) (E, E’). A similar pectoral fin was found in a DMSO-treated embryo (n = 9). Pectoral fins of Notch signalling disrupted embryos such as mibta52b (n = 18) (B, B’), jagged2 (n = 10) (C, C’) and Su(H)1+2 (n = 12) (D, D’) morphants and DAPT-treated embryos (n = 10) (F, F’) showing disorganized endoskeletal disc cells. cl, chleitrum; ed, endoskeletal disc; ff, fin fold.<ref name="PMID23840804"/>]]<br />
|}<br />
<br><br><br />
<br />
====Quiz Your Notch-Knowledge on Animal Development!====<br />
<br />
<quiz display=simple><br />
<br />
{In which animal (as described in this section) has it been shown that defective notch signalling leads to thinning and fragmentation of skeletal muscle fibres?<br />
|type="()"}<br />
- &nbsp; Drosophila melanogaster<br />
- &nbsp; I don't know!<br />
- &nbsp; Caenorhabditis elegans<br />
+ &nbsp; Danio rerio<br />
|| Remember, it was observed in one study that the skeletal muscle fibres of zebrafish (Danio rerio) were thin and fragmented and the structure of their sarcomeres were significantly compromised.<ref><pubmed>23840804</pubmed></ref> <br />
</quiz><br />
<br />
===Summary of Functions of Proteins Involved in Notch Signalling <small>(adapted from Table 1<ref name="PMID17761886"><pubmed>17761886</pubmed></ref>)</small>===<br />
{| class="pretty table"<br />
|-bgcolor="a3bfb1"<br />
| '''Mammals'''<br />
| '''''Drosophila'''''<br />
| '''''C.elegans'''''<br />
| '''Function'''<br />
|-bgcolor="F5FFFA" <br />
| Notch 1-4<br />
| Notch<br />
| Lin-12, Glp-1<br />
| Single transmembrane receptor and transcription factor<br />
|-<br />
| Delta 1, Delta3-4, Jagged1-2<br />
| Delta, Serrate<br />
| APX-1, LAG-2, ARG-1, DSL-1<br />
| Single transmembrane ligands of the Notch receptor<br />
|-bgcolor="F5FFFA" <br />
| CBF1/RBPJK<br>Mastermind1-3<br />
| Su(H)<br>Mastermind<br />
| Lag-1<br>Lag-3<br />
| DNA-binding transcription factor<br>Transcriptional co-activator<br />
|-<br />
| Lunatic, manic, and radical Fringe<br />
| Fringe<br />
|<br />
| Modifies both Notch and its ligands<br />
|-bgcolor="F5FFFA" <br />
| ADAM10, ADAM17<br />
| Kuzbanian, Kuzbanian-like, TACE<br />
| SUP-17, ADM-4<br />
| Metalloproteases targeting S2 Notch cleavage sites<br />
|-<br />
| Presenilin 1-2, nicastrin, APH1, PEN2<br />
| Presenilin, nicastrin, APH1, PEN2<br />
| SEL-12, APH-1, APH-2, PEN2<br />
| Proteins of the γ-secretase complex, which targets Notch S3 and S4 cleavage sites<br />
|-bgcolor="F5FFFA" <br />
| Mind bomb, skeletrophin, neuralized 1-2<br />
| Mind bomb 1-2, neuralized<br />
| Y47D3A.22<br />
| E3 ubiquitin-protein ligases that targets Delta and Jagged/Serrate and regulate their endocytosis<br />
|}<br />
<br><br />
<br />
===Abnormalities in Notch Signalling===<br />
Mutations in Notch genes and hence defects in Notch signalling have been implicated in the pathogenesis of several inherited diseases in humans.<ref name="PMID23729744">As reviewed by <pubmed>23729744</pubmed></ref><ref name="PMID22306179">As reviewed by <pubmed>22306179</pubmed></ref> The diseases listed in this summary table are only a few examples and are described in more detail below.<br />
<br><br />
<br />
{| class="pretty table"<br />
|-bgcolor="CEDFF2" <br />
| '''Disease'''<br />
| '''Gene'''<br />
| '''Phenotype'''<br />
|-bgcolor="F5FAFF" <br />
| Alagille syndrome ([http://omim.org/entry/118450 OMIM118450], [http://omim.org/entry/610205 OMIM610205])<br />
| ''JAG1'', ''NOTCH2''<br />
| Developmental abnormalities of the heart, liver, eye, and skeleton. Neonatal jaundice and cholestasis are early symptoms.<br />
|-<br />
| CADASIL ([http://omim.org/entry/125310 OMIM125310])<br />
| ''NOTCH3''<br />
| Autosomal vascular disorders linked to ischemic strokes, dementia, and premature death.<br />
|-bgcolor="F5FAFF"<br />
| T-cell acute lymphoblastic leukaemia ([http://omim.org/entry/613065 OMIM613065])<br />
| ''NOTCH1'' (mutation in heterodimerization domain or PEST domain)<br />
| Tumour derived from T-cell progenitors. Symptoms include anaemia and enlargement of lymph nodes in the liver and/or spleen.<br />
|-<br />
| Spondylocostal dysostosis ([http://omim.org/entry/122600 OMIM122600])<br />
| ''DLL3'', Lunatic fringe<br />
| Vertebral segmentation defects as well as rib abnormalities.<br />
|}<br />
<br />
====Alagille Syndrome====<br />
Alagille syndrome (AGS) is an autosomal dominant, multisystem disorder that mainly affects the liver, heart, and kidney. Diagnostic characteristics of the disease include liver disease, cardiac disease, vertebral defects, eye conditions, and facial features, as well as renal and vascular abnormalities.<ref>As reviewed by <pubmed>26548814</pubmed></ref> Two variants of AGS, type 1 and type 2, have been identified, and each is related to different defects in the Notch pathway. In clinically diagnosed cases of AGS type 1 (which accounts for approximately 97% of all cases of AGS), a mutation in the gene encoding the Notch ligand Jagged1 (Jag1) has been identified as a contributing factor.<ref>As reviewed by <pubmed>11745040</pubmed></ref> In the much rarer AGS type 2, a mutation in the NOTCH2 gene has been implicated in the manifestation of AGS. The mechanisms by which mutations in JAG1 and NOTCH2 lead to pathogenesis of AGS are not well understood, but it is known that normal Notch signalling is important in angiogenesis. Therefore, it is thought that abnormal JAG1 or NOTCH2 will cause disruptions to the pathway that leads to the vascular disorders present in AGS. This is also evidenced by research that JAG1 knockout mice suffer premature death due to vascular defects.<ref>As reviewed by <pubmed>21934706</pubmed></ref> It is possible that AGS caused by a mutation in NOTCH2 alone will lead to a different presentation than AGS patients with mutated JAG1; however, this is still undergoing further research. It is also unclear why AGS type 2 occurs at a significantly lower incidence than AGS type 1.<ref><pubmed>16773578</pubmed></ref><br />
<br><br><br />
<br />
====Spondylocostal Dysostosis====<br />
Spondylocostal Dysostosis (SD) is a collective term for conditions characterised by anomalies relating to rib and spine. The vertebrae are fused and shaped abnormally which can result in scoliosis. Similarly, the ribs may also be fused together or in some cases completely missing. As a result, people with this condition have short trunk dwarfism where their bodies are short in stature but have normal length limbs. Genetic changes are known to cause SD. SD Type 1 is the most prevalent form of this disease which is caused by the mutation in the delta like canonical Notch ligand 3 (DLL3 gene).<ref><pubmed>10742114</pubmed></ref> DLL3 provides the information for making a protein that regulates the Notch signalling pathway. The DLL3 protein in conjunction with the Notch pathway is primarily responsible for preventing the fusion of future vertebrae in a process known as somite segmentation.<ref><pubmed>11236715</pubmed></ref> An interruption in the Notch pathway inhibits the somite segmentation resulting in abnormalities relating to the ribs and spine as seen in SD. 25 percent of SD arise from mutations in the identified genes and further research suggest that other genes involved in the Notch signalling pathway may also be related to SD.<br />
<br><br><br />
<br />
====Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)====<br />
CADASIL is an autosomal-dominant disease of the small to medium-sized arteries, mainly in the brain, that leads to dementia and disability in mid-life. The symptoms, age of onset, and prognosis are variable. Distinguishing symptoms include subcortical ischemic events (60-80% of cases), cognitive impairment (60% of late stage disease), migraines (30-40%), mood disturbances (30%), and apathy (40%).<ref name="PMID21045164"><pubmed>21045164</pubmed></ref><ref name="PMID20301673"><pubmed>20301673</pubmed></ref> Approximately 5-10% of CADASIL patients also experience seizures. The mean age of onset is 45 years of age and the disease duration is between 10–40 years. More than 95% of CADASIL cases present with pathogenic mutations in NOTCH3 (located on chromosome 19p13), specifically the epidermal growth factor-like repeat domain.<ref name="PMID20301673"/><ref><pubmed>24579972</pubmed></ref> The NOTCH3 gene is involved in the normal development of blood vessels in both fetal and adult brains. In adults, NOTCH3 is expressed in the smooth muscle cells of arteries.<ref name="PMID21045164"/> There is currently no effective treatment available for CADASIL.<br />
<br><br><br />
<br />
====Congenital Heart Defects====<br />
<br />
'''Aortic Valve Disease'''<br />
<br />
[[File:Aortic valve disease.jpg|thumb|450px|right|alt=Loss of NOTCH1 expression in proximity to calcific nodules in human aortic valves|'''Loss of NOTCH1 expression in proximity to calcific nodules in human aortic valves.''' (A) Representative sections from control (A,B) and diseased (C-F) aortic valve cusps. (B) is high magnification image of boxed area in (A) and (D,E) are higher magnification of region in (C) while image in (F) shows another calcified aortic valve. Expression of Notch1 intracellular domain (NICD) is found in the thickened fibrosa of diseased aortic valve (C,E) as compared to the acellular fibrosa of control valves (A,B). However, there is significant loss of NICD expression in cells residing adjacent to calcific nodules (D,F). The fibrosa is oriented upward in all panels, and scale bars equal 100 microns (B,D,E,F are at same magnification). Brown signal represents NICD expression while nuclei are counterstained in blue.<ref name="PMID22110751"><pubmed>22110751</pubmed></ref>]]<br />
<br />
Calcification of the aortic valve is a leading cause of adult heart disease. Mutations in NOTCH1 have been found to cause various aortic valve abnormalities, including the development of a bicuspid aortic valve (as opposed to tricuspid) and valve calcification.<br />
<br />
&emsp;&emsp;A study by Garg et al. (2005) looked at mouse embryos and the expression of ''Notch1'' during development. It was found that during normal embryonic development, ''Notch1'' was abundantly expressed in the outflow tract mesenchyme (which develops into the heart valves) and the endocardium, as well as in the endothelial layer and mesenchyme of the aortic valve leaflets at the time of arterial trunk septation. Abnormal ''Notch1'' led to the death of mice from vascular endothelial defects. Garg et al. then investigated whether NOTCH1 was involved in calcium deposition and therefore valve calcification. This is thought to be due to differentiation of valve cells into osteoblast-like cells. This leads to the upregulation of osteopontin, osteocalcin, and other osteoblast-specific genes, which is normally regulated by the transcription factor Runx2. Runx2 is known to be upregulated in animal models of valve calcification. Garg et al. found that Notch1 was capable of repressing Runx2 activation. Heart tissue and vasculature are normally abundant with the hairy-related transcriptional repressors Hrt1 and Hrt2 (also called Hey1 and Hey2), which are normally activated by Notch and are key mediators of the Notch pathway. Hrt1 and Hrt2 were both expressed in the endothelium of the mice aortic valve leaflets, the endocardium, and the vascular endothelium. They were found to inhibit the activation of osteoblast-specific genes by Runx2. It was thought that Hrt proteins can repress Runx2 by physical interaction as well as mediate Notch1 repression of Runx2. Therefore, a defect in Notch will cause upregulation of Runx2, due to the lack of repressor activity by Notch itself and the activation of the repressors Hrt1 and Hrt2. This leads to the expression of osteoblast genes that results in the differentiation of valvular cells into osteoblast-like cells and ultimately causes aortic valve calficiation.<ref><pubmed>16025100</pubmed></ref><br />
<br />
The picture to the right is a histological image of aortic valve disease from a study performed in rats investigating molecular changes that occurred when Notch signalling was suppressed in the aortic valve.<ref name="PMID22110751"/><br />
<br><br><br />
<br />
====Tumourigenesis====<br />
Notch has been shown to be involved in cancer development and can act as both an oncogene and a tumour suppressor gene.<ref>As reviewed by <pubmed>14570040</pubmed></ref><ref name="PMID23729744"/> Defective Notch signalling has been implicated in the pathogenesis of several human cancers, such as acute myelogenous leukemia (overexpression of Jagged1 and Notch1), multiple myeloma (overexpression of Jagged1/2 and Notch1/2), and B-cell–derived Hodgkin lymphoma (overexpression of Jagged1 and Notch1).<ref name="PMID16291593">As reviewed by <pubmed>16291593</pubmed></ref><br />
<br />
Elevated levels of Notch ligand proteins and/or mRNA have been observed in several cancers. Upregulated Jagged1 mRNA has been seen in human pancreatic cancer; Jagged1 protein overexpression has also been studied in prostate, cervix, and brain cancers. Cervical cancers have shown upregulated Jagged2 mRNA. Additionally, elevated Dll1 mRNA has been observed in cervical cancers, as well as in human brain cancers at both Dll1 mRNA and protein levels. Additionally, defective Notch receptor expression has been implicated in cancer as well. For example, elevated Notch1 protein expression has been found in cervical, colon, lung, pancreas, skin, and brain cancers. Protein overexpression of Notch3 and Notch4 has also been seen in malignant melanoma and pancreatic cancer.<ref name="PMID16291593"/><br />
<br />
Interestingly, research has shown that Notch signalling can also have a tumour-suppressive effect. Studies have indicated that Notch signalling can inhibit proliferation and even stimulate apoptosis in malignant B-cells. Furthermore, the Notch1 intracellular domain has also shown the ability to induce growth arrest and apoptosis in Hodgkin lymphoma and multiple myeloma cells.<ref name="PMID16291593"/><br />
<br><br><br />
<br />
'''T-Cell Acute Lymphoblastic Leukaemia'''<br><br />
T-cell acute lymphoblastic leukaemia (T-ALL) is an example of how abnormal Notch signalling can lead to the development of cancer. T-ALL is an aggressive childhood cancer of the immune system's T-cells. The NOTCH1 gene encodes the Notch1 receptor, which is involved in the determination of pluripotent cell progenitors to T-cells and the organisation of these cells in the developing thymus. Activating mutations in the extracellular domain and/or the C-terminal PEST domain of Notch1 have been identified in more than half of all cases of T-ALL.<ref><pubmed>15472075</pubmed></ref><br />
<br><br><br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Other Examples of Roles of Notch in Cancer <small>(adapted from ''Notch in disease''<ref name="PMID23729744"/>)</small><br />
|-<br />
|-bgcolor="a3bfb1"<br />
| '''Gene'''<br />
| '''Role of Notch'''<br />
| '''Disease'''<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br>''NOTCH2''<br />
| Oncogene<br>Tumour suppressor<br />
| Pancreatic ductal adenocarcinoma<br />
|-<br />
| ''NCSTN''<br>''MAML1''<br>''APH1A''<br>''NOTCH2''<br />
| Tumour suppressor<br />
| Chronic myelomonocytic leukaemia<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br />
| Oncogene<br />
| Chronic lymphocytic leukaemia<br />
|-<br />
| Activated NOTCH<br />
| Tumour suppressor<br />
| Hepatocellular carcinoma<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br>''NOTCH2''<br>''NOTCH3''<br />
| Tumour suppressor<br />
| Head and neck squamous cell carcinoma<br />
|-<br />
| NOTCH<br />
| Tumour suppressor<br />
| B-cell acute lymphoblastic leukaemia<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br />
| Oncogene<br />
| Non-small-cell lung cancer<br />
|-<br />
| ''NOTCH1''<br />
| Oncogene<br />
| T-cell acute lymphoblastic leukaemia<br />
|}<br />
<br><br />
<br />
====Quiz Your Notch-Knowledge on Abnormalities in Notch Signalling!====<br />
<br />
<quiz display=simple><br />
{ What is the name for the collection of rib and spine abnormalities that result from interruption in the Notch pathway that leads to inhibition of somite segmentation in the embryo?<br />
|type="()"}<br />
- &nbsp; Alagille Syndrome<br />
- &nbsp; T-cell acute lymphoblastic leukaemia<br />
+ &nbsp; Spondylocostal Dysostosis<br />
- &nbsp; CADASIL<br />
|| Remember, Spondylocostal Dysostosis is a collective term for conditions characterised by anomalies relating to rib and spine. Genetic changes lead to an interruption in the Notch pathway that inhibits the somite segmentation resulting in abnormalities relating to the ribs and spine. Alagille syndrome is an autosomal dominant, multisystem disorder that mainly affects the liver, heart, and kidney. T-cell acute lymphoblastic leukaemia is an aggressive childhood cancer of the immune system's T-cells. CADASIL is an autosomal-dominant disease of the small to medium-sized arteries, mainly in the brain, that leads to dementia and disability in mid-life.<br />
</quiz><br />
<br />
===Current Areas of Research and Future Directions===<br />
Notch has been identified as having a role in the development of several cancers, and therefore research has recently begun investigating the use of Notch inhibitors in cancer treatment.<ref>As reviewed by <pubmed>27732970</pubmed></ref> γ-secretase inhibitors (GSIs), which inhibit the normal cleavage of Notch at the cell membrane and hence NICD release, have been a popular area of research. In the specific case of desmoid tumours, it was observed that treatment GSIs resulted in decreases in NICD and Hes1 expression in the tumour cells. Overall, tumour cell migration and invasion were decreased and cell growth was also inhibited.<ref><pubmed>26349011</pubmed></ref> GSIs have also been shown to have an inhibitory growth effect on pancreatic, breast, and lung cancers, but unfortunately they also produce side effects ''in vivo''.<ref>As reviewed by <pubmed>27688721</pubmed></ref> Therefore continued study into GSIs is required to make them safe for human treatment. Ultimately, with ongoing research, it is possible that the Notch pathway will eventually become an effective therapeutic target for cancers.<br />
<br><br><br />
<br />
<big><b>To search and read recent PubMed research and review articles on Notch, click <u>[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=Notch here]</u>!</b></big><br />
<br><br><br />
<br />
===Want to Read More About Notch?===<br />
The [http://www.omim.org/ OMIM (Online Mendelian Inheritance in Man) database] contains extensive information about the Notch genes and associated proteins and is a great place to go if you want to find out more about the Notch pathway in humans! Click on these links to learn more about the Notch genes that encode the human receptors and ligands:<br />
<li>[http://www.omim.org/entry/190198 NOTCH1] | [http://www.omim.org/entry/600275 NOTCH2] | [http://www.omim.org/entry/600276 NOTCH3] | [http://www.omim.org/entry/164951 NOTCH4]<br />
<li>[http://www.omim.org/entry/601920 JAG1] | [http://www.omim.org/entry/602570 JAG2]<br />
<li>[http://www.omim.org/entry/606582 DLL1] | [http://www.omim.org/entry/602768 DLL3] | [http://www.omim.org/entry/605185 DLL4]<br />
<br><br><br />
<br />
You can also look at these papers for examples of reviews and research papers that reinforce the diversity of how the Notch pathway functions in organisms.<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch influences adult development as well!</big><br />
|-<br />
|Interestingly, Notch does not only play a role in human embryonic development, but has also been found to influence developmental processes after birth. One of these processes is neurogenesis, for example.<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159580/ '''Not(ch) just development: Notch signalling in the adult brain.'''] <br />
<br />
This review explains that the Notch signalling pathway, which is so often regarded as a major molecular player in development, actually has important functions related to neural cells in the adult. As you would have read in the [[#Abnormalities in Notch signalling| Abnormalities in Notch Signalling]] section, Notch abnormalities are involved in a number of diseases, which underlines its importance in maintaining adult brain function. Some highlights of this review are: Figure 2 provides a schematic representation of precise roles Notch activation can play in the adult brain; explanations of the ways that Notch influences brain plasticity; and the discussion of conflicting results of studies exploring the role of Notch in stroke recovery.<ref name=PMID21505516><pubmed>21505516</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch Modulation for Therapy</big><br />
|-<br />
|As you would have read in the [[#Abnormalities in Notch signalling| Abnormalities in Notch Signalling]] section, Notch can play different roles in cancer development. An interesting review further elucidates that modulation of Notch signalling is actually being investigated as a potential target for cancer therapy:<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704338/ '''Targeting the Notch signaling pathway in cancer therapeutics'''] <br />
<br />
This articles focuses on reviewing data emerging from recent research, explaining how Notch contributes to the development of a number of cancers, and then outlining the current focuses of investigations into how to therapeutically manipulate the Notch pathway. Some highlights from this review are: the detailed description of how Notch interacts with other signalling pathways such as Wnt and the signalling cytokine Interleukin-6; explanations of the seemingly conflicting roles of Notch as a tumour promoter and suppressor; and discussion of the findings of various Notch-related studies in cancer stem cells.<ref name=PMID26767041><pubmed>26767041</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch influences reproduction in worker honey bees!</big><br />
|-<br />
| In our [[#Roles in Animal Development| Roles in Animal Development]] section we discussed Notch in relation to a number of animals, however one that we did not cover was the worker honey bee, or ''Apis mellifera''. A recent study shows that Notch also plays a role in these honeybees!<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976197/ '''Notch signalling mediates reproductive constraint in the adult worker honeybee.'''] <br />
<br />
This research paper essentially concludes that in the worker honeybee Notch signalling constrains reproduction between males and females; they were the first team to elucidate a molecular mechanism underlying the link between adult ovary activity in bees and the presence of the queen bee. Some highlights from this unique and interesting study are: the background explanation that female worker bees have suppressed activity due to pheromones produced by the queen; the finding that Notch plays a part in this inactivation of reproductivity; and the discussion about social control of reproduction and evolution.<ref name=PMID27485026><pubmed>27485026</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch signalling is involved in embryo implantation!</big><br />
|-<br />
| Notch is essential for many developmental embryonic processes, as described in our [[#Roles in Embryonic Development|Roles in Embryonic Development]] section. Interestingly, research has shown that Notch signalling also has an important role in the initial process of establishing a successful pregnancy. Specifically, normal Notch signalling has been seen to be a critical factor in fetal-maternal communication during implantation and placentation. (To read more about these processes, go to these pages on [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Week_1_and_2_Development Weeks 1-2] and [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Week_3_Development Week 3] of development.)<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/24357662 '''Fetal-maternal communication: the role of Notch signalling in embryo implantation.''']<ref>As reviewed by <pubmed>24357662</pubmed></ref><br />
<br />
This review describes both human and animal studies of Notch signalling during pregnancy. It explains research of Notch signalling at the human blastocyst-maternal interface, and that Notch signalling has been observed in both the maternal endometrium and the blastocyst. Furthermore, Notch signalling is also important for the processes of implantation and placentation. Overall, the review summarises findings of Notch signalling in endometrial-trophectoderm interactions during the implantation, regulation of extravillous trophoblast invasion and spiral artery remodelling in the decidua, and angiogenesis in the placenta, as well as how abnormal Notch signalling is related with impaired placentation and pre-eclampsia.<br />
|}<br />
<br><br />
<br />
===Glossary===<br />
{| class="pretty table"<br />
|-<br />
| '''AER'''<br />
| 'Apical Ectodermal Ridge' is a structure that forms from the ectodermal cells at the distal end of each limb bud. The AER acts as a major signalling centre in order to ensure proper limb development.<br />
|-<br />
| '''Apoptosis'''<br />
| Programmed cell death which occurs in the development of many systems.<br />
|-<br />
| '''Calcification'''<br />
| The accumulation of calcium salts in body tissue. It normally occurs in the formation of bone, but abnormally calcium can be deposited in soft tissue causing it to harden.<br />
|-<br />
| '''Cardiogenic'''<br />
| From cardiogenesis - meaning formation of the heart.<br />
|-<br />
| '''Cardiomyocyte'''<br />
| The muscle cells (myocytes) that make up the cardiac muscle<br />
|-<br />
| '''Congenital'''<br />
| (Of a disease or physical abnormality) present from birth.<br />
|-<br />
| '''Craniofacial'''<br />
| Meaning relating to the cranium and the face.<br />
|-<br />
| '''Cyclin D1'''<br />
| A protein required for progression through the G1 phase of the cell cycle. Read more about it [https://en.wikipedia.org/wiki/Cyclin_D1 here], or see information on its encoding gene here: [http://omim.org/entry/168461 OMIM168461].<br />
|-<br />
| '''Endocardial'''<br />
| From endocardium - meaning the thin, smooth membrane which lines the inside of the chambers of the heart and forms the surface of the valves.<br />
|-<br />
| '''Endocrine'''<br />
| As in the endocrine system, refers to glands that secrete hormones or other substances directly into the blood.<br />
|-<br />
| '''Epithelium'''<br />
| The thin tissue that forms the outer layer of a body's surface and also lines the alimentary canal and other hollow structures.<br />
|-<br />
| '''Gastrulation'''<br />
| Describes the formative process of the formation of the trilaminar embryo containing the three germ layers.<br />
|-<br />
| '''Gliogenesis'''<br />
| The formation and development of glial cells (astrocytes, oligodendrocytes, Schwann cells, microglia).<br />
|-<br />
| '''Haematopoietic'''<br />
| From haematopoiesis - meaning the formation of blood cellular components<br />
|-<br />
| '''Haploinsufficiency'''<br />
| When a diploid organism has only a single functional copy of a gene (with the other copy inactivated by mutation), and so the total level of a gene product (a particular protein) produced by the cell is about half of the normal level.<br />
|-<br />
| '''Homeostasis'''<br />
| The ability to maintain a constant internal environment in response to environmental changes.<br />
|-<br />
| '''Ligand'''<br />
| A molecule that binds to a specific binding site on a protein (receptor).<br />
|-<br />
| '''Mef2C promoters'''<br />
| Myocyte-specific enhancer factor 2C is a transcription factor in the Mef2 family that is encoded by the gene ''MEF2C'' in humans ([https://omim.org/entry/600662 OMIM 600662]). This gene is involved in cardiac morphogenesis and myogenesis, as well as vascular development. It is thought to also possibly play a role in neurogenesis.<br />
|-<br />
| '''Mesenchymal'''<br />
| From mesenchyme - meaning a loosely organised, mainly mesodermal embryonic tissue which develops into connective and skeletal tissues, including blood and lymph.<br />
|-<br />
| '''Morphogenesis'''<br />
| Refers to the origin and development of morphological characteristics.<br />
|-<br />
| '''Myogenic'''<br />
| From myogenesis - meaning formation of muscle.<br />
|-<br />
| '''Myogenin'''<br />
| Also known as myogenic factor 4, this is a muscle-specific basic-helix-loop-helix transcription factor involved in the coordination of skeletal muscle development or myogenesis and repair.<br />
|-<br />
| '''Neural Crest'''<br />
| In vertebrate embryos, this is a transient structure that gives rise to most of the peripheral nervous system and to a number of non-neural cell types such as the smooth muscle cells of the cardiovascular system. <br />
|-<br />
| '''Neurogenic'''<br />
| From neurogenesis - meaning the formation of nervous tissue.<br />
|-<br />
| '''Neurulation'''<br />
| The folding process in vertebrate embryos whereby the neural plate transforms into the neural tube.<br />
|-<br />
| '''NICD'''<br />
| Notch intracellular domain<br />
|-<br />
| '''Oncogenic'''<br />
| From oncogenesis, also known as tumorigenesis or carcinogenesis - meaning the formation of a cancer, whereby normal cells are transformed into cancer cells.<br />
|-<br />
| '''Paracrine'''<br />
| A hormone that exerts an effect only in the vicinity of the gland secreting it.<br />
|-<br />
| '''Protease'''<br />
| An enzyme which breaks down proteins and peptides.<br />
|-<br />
| '''Runx2'''<br />
| Runt-related transcription factor 2 is a protein that in humans is encoded by the ''RUNX2'' gene ([http://omim.org/entry/600211 OMIM600211]). RUNX2 is an important transcription factor associated with osteoblast (bone substance-secreting cells) differentiation.<br />
|-<br />
| '''Stromal cells'''<br />
| The connective tissue cells of any organ. They support the function of the parenchymal cells of that organ. Fibroblasts and pericytes are among the most common types of stromal cells.<br />
|-<br />
|}<br />
<br />
====Further Glossary Links====<br />
[[A|A]] | [[B|B]] | [[C|C]] | [[D|D]] | [[E|E]] | [[F|F]] | [[G|G]] | [[H|H]] | [[I|I]] | [[J|J]] | [[K|K]] | [[L|L]] | [[M|M]] | [[N|N]] | [[O|O]] | [[P|P]] | [[Q|Q]] | [[R|R]] | [[S|S]] | [[T|T]] | [[U|U]] | [[V|V]] | [[W|W]] | [[X|X]] | [[Y|Y]] | [[Z|Z]] | [[Numbers|#]]<br />
<br />
===References===<br />
<references/></div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=2016_Group_Project_2&diff=255180
2016 Group Project 2
2016-10-27T08:25:06Z
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<hr />
<div>{{ANAT2341Project2016header}}<br />
{{Group Assessment Criteria table}}<br />
<!-- Do not delete the above template from the Group project page. --><br />
=The Notch Signalling Pathway=<br />
===Introduction===<br />
The Notch signalling pathway is the most prevalent form of intracellular communication in multicellular organisms. It is a critical pathway for cell differentiation, proliferation, and apoptosis. It is involved in embryonic organ development through the regulation of cell-cell signalling; specifically lateral inhibition, formation of boundaries, and cell lineage assignation.<ref name="The Developing Human">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2015). The developing human: clinically oriented embryology (10th ed.). Philadelphia: Saunders.</ref><ref name="PMID10075488">As reviewed by <pubmed>10075488</pubmed></ref> This pathway is also actively involved in adjacent cell communication, developmental process such as adult homeostasis, and stem cell maintenance. Since this pathway is an intricate and crucial aspect of an organism's development and cell signalling, a mutation in the functional components of this pathway can cause a myriad of diseases such as congenital disorders, cancers, strokes, Alagille syndrome, and leukoencephalopathy.<ref name="PMID19255248">As reviewed by <pubmed>19255248</pubmed></ref> The process of Notch signalling primarily utilises a ligand-receptor interaction to release protein fragments at the cellular membrane, which then provide signals to the internal environment of the cell and to adjacent cells. In mammals, the Notch signalling pathway is comprised of four receptors (Notch 1-4) which interact with Delta or Jagged ligands to bring about the activation of this pathway. Homologous Notch genes have been identified in other animals, such as ''Drosophila melanogaster'' (fruit fly) and ''Danio rerio'' (zebrafish).<br />
<br><br />
<br />
<big>What will you find on this wiki page?</big><br />
<br />
This page is designed to provide an overview of such features of the Notch signalling pathway, but is in no way a complete resource for all Notch-related information (especially since this signalling pathway has such a wide array of activities in many organisms and the scientific understanding of it is continuously updating!). By reading this page you should come to a better understanding of Notch in regards to: general molecular mechanisms; embryonic development by systems; examples of animal development; abnormalities and disease; current and potential future research; as well as a couple of links to interesting articles for those who want to read more. There is a [[#Glossary| Glossary]] at the bottom of the page for better understanding of scientific terms used throughout this page, and readers are encouraged to 'expand' any collapsed information on the page to optimise their experience in reading about Notch. <br />
<br><br><br />
<div align="center"><html5media width="560" height="315">https://www.youtube.com/embed/axkDX0XZyN0</html5media></div><br />
<br><br />
<br />
===History===<br />
{| class="pretty table"<br />
|-bgcolor="FAF5FF" <br />
| 1914<br />
| First description of a "notch" defect (loss of tissue in the wing) in ''Drosophila'' by John S. Dexter, giving the gene its name<ref>Dexter, J. (1914). The Analysis of a Case of Continuous Variation in Drosophila by a Study of Its Linkage Relations. ''The American Naturalist'', 48(576), 712-758. Retrieved from http://www.jstor.org/stable/2455888</ref><br />
|-<br />
| 1917<br />
| First allele of ''Notch'' is identified by Thomas Hunt Morgan<ref>Morgan, T. H. (1917). The theory of the gene. ''The American Naturalist'', 51(609), 513-544.</ref><br />
|-bgcolor="FAF5FF" <br />
|-<br />
| 1930s<br />
| Donald F. Poulson conducts research into the involvement of ''Notch'' in development.<ref><pubmed>16588136</pubmed></ref> <br />
|-<br />
| 1958<br />
| An investigation by W.J. Welshons confirmed that the locus of Notch is contained within the 3C7 band of the X chromosome.<ref><pubmed>13635554</pubmed></ref><br />
|-bgcolor="FAF5FF" <br />
|-<br />
| 1983<br />
| DNA sequences belonging to the Notch locus cloned and determined that RNA is required for the function of the wild type Notch. Further insight developed into the function of Notch and its role in differentiation and regeneration.<ref><pubmed>6403942</pubmed></ref><br />
|-<br />
| 1986<br />
| The molecular analysis and sequence of the Notch locus was determined by Michael W. Young and his team. A relationship was identified between the protein encoded by the major Notch transcript and mammalian clotting and growth factors.<ref><pubmed>3097517</pubmed></ref><br />
|-bgcolor="FAF5FF" <br />
|-<br />
| 1989<br />
| Neurogenic loci "Delta" and "Mastermind" identified and research conducted to search for genes which may have an interaction with the Notch protein. It was confirmed that mutations in these loci will affect neurogenesis.<ref><pubmed>2338245</pubmed></ref><br />
|-<br />
| 2012<br />
| PA6 cells expressed the Notch ligand Jag1 and showed that Notch signalling inhibition pathway interrupted the ability for differentiation to occur in PA6 cells. <ref><pubmed>22558462</pubmed></ref><br />
|}<br />
<br />
===Overview of Molecular Mechanisms===<br />
Mammals possess a total of four ''Notch'' genes, with five genes for encoding the associated ligands, Delta-like and Jagged. The ''Notch'' genes each code for a single transmembrane receptor. Extracellularly, it contains epidermal growth factor (EGF)-like repeats for ligand interaction and Lin-12-Notch (LN) repeats for regulating the interactions between the extracellular and intracellular regions. Intracellularly, Notch has seven ankyrin (ANK) repeats and a transactivation domain (TAD), as well as a proline, glutamine, serine, threonine-rich (PEST) domain for degradation of Notch.<br />
<br><br><br />
[[File:Notch structure cartoon.jpg|thumb|700px|center|'''The structure of the Notch receptor.'''<ref name="PMID19255248"/> Extracellularly there are epidermal growth factor (EGF)-like repeats and Lin-12-Notch repeats (LNRs). The Notch intracellular domain (NICD) is made up of a rRBP-Jkappa-associated module (RAM) domain, ankyrin (ANK) repeats, and a proline, glutamine, serine, threonine-rich (PEST) domain. There are three sites for cleavage by enzymes: S1, S2, and S3/S4.]]<br />
<br />
====Canonical pathway====<br />
[[File:Overview of Notch signalling.png|thumb|500px|'''Summary of canonical Notch signalling.''' The interaction between Delta-like or Serrate ligands (DSL) and the Notch receptor on an adjacent cell initiates proteolytic cleavage of Notch and the release of the Notch intracellular domain (NICD). The NICD is then transported to the nucleus where it can induce transcription of Notch target genes by binding to specific proteins (MAM, CSL).<ref><pubmed>27404588</pubmed></ref>]]<br />
The canonical Notch pathway is unique in that it involves direct interaction between adjacent cells, as opposed to paracrine signalling, because both the Notch ligands and Notch receptors are transmembrane proteins found in the cell membrane. Furthermore, the lack of a secondary messenger or amplification process means that the Notch pathway has limited opportunities for regulation and must therefore be tightly controlled. Depending on its developmental and cellular context, activation or inhibition of the pathway can result in a variety of cellular responses, including cell death, proliferation, or differentiation.<ref name="Introduction to Notch Signalling">Yamamoto, S., Schulze, K.L. & Bellen, H.J. (2014). Introduction to Notch Signalling. ''Notch Signaling: Methods and Protocols''. Methods in Molecular Biology: 1187</ref><br />
<br><br><br />
Four Notch proteins are involved in the canonical pathway. NOTCH1 to NOTCH4 are single transmembrane receptors and can interact with a variety of ligands, including NOTCH ligands (e.g. Delta ligands) and Serrate ligands. There are three Delta ligands (Dll1, Dll3, and Dll4) and two Serrate ligands (Jagged1 and Jagged2) present in mammals.<ref name="Introduction to Notch Signalling"/> The binding between the Notch receptor and the ligand on the adjacent cell induces the release of the Notch intracellular domain (NICD) via a sequence of proteolytic reactions.<ref name="The Developing Human"/> Cell-cell interaction is therefore critical in the process of triggering Notch signalling.<br />
<br><br><br />
The interaction on the cell surface between Notch and its ligand on an adjacent cell causes the extracellular metalloprotease site (S2 site) to be exposed. The S2 site is then cleaved by transmembrane proteases belonging to the a disintegrin and metalloproteinase/tumour necrosis factor α converting enzyme (ADAM/TACE) family. The remaining Notch fragment subsequently undergoes two more intramembranous cleavages at the S3/S4 sites by the γ-secretase complex. Finally, the NICD is released and enters the nucleus to interact with CSL (CBF1, Suppressor of Hairless, Lag-1) and Mastermind-like proteins (MAMLs). CSL is a DNA-binding protein that acts as a transcription factor by forming repressor or activator complexes; in the absence of the NCID, CSL is bound to corepressor proteins (CoR) that prevent transcription of Notch target genes. MAMLs are transcriptional co-activators that are required for transcription of the target genes, hence they are involved in the regulation of the pathway.<ref name=PMID10075488/><ref name="Introduction to Notch Signalling"/> To stop signalling, the NICD is phosphorylated by kinases and ubiquitinated by E3 ubiquitin ligases, which results in proteasome mediated degradation and subsequent termination of the signal.<ref name="Introduction to Notch Signalling"/><br />
<br><br><br />
<br />
====Non-canonical pathway====<br />
Immense research has been carried out on the canonical Notch pathway and its members are well known. While canonical notch ligands control most of the known Notch signalling, a group of structurally distinct non-canonical ligands exist which activate Notch and its pleiotropic effects. Notch can non-canonically carry out its functions by post-translationally targeting Wnt/β-catenin signalling. This type of signalling is CSL-independent and can also work independently of ligands. Some genes are affected by the non-canonical Notch signalling, however their mediators in most cases are unknown. Notch binds and titrates levels of active β-catenin. Therefore, active β-catenin activity may serve as a useful readout for non-canonical Notch signals.<ref name="PMID22397947">As reviewed by <pubmed>22397947</pubmed></ref> <br />
<br />
Recent research has shown that Notch signalling plays crucial roles for cellular differentiation during development through γ-secretase-dependent intramembrane proteolysis followed by transcription of target genes. Hayashi et al. (2016) uncovered a ligand-dependent but γ-secretase-independent, non-canonical Notch signalling involved in presynaptic protein expression in postmitotic neurons.<ref name="PMID27040987"><pubmed>27040987</pubmed></ref><br />
<br><br><br />
<br />
====Transcriptional regulation of Notch signalling====<br />
A number of genes have been found to act as modulators of Notch signalling by modifying the ability of Notch to interact with its ligands. These include proteins acting extracellularly (Fringe, Brainiac, Egghead, Scabrous, Wingless), proteins acting at the cell membrane (Big brain), proteins acting intracellularly (Numb, Sanpodo, Disabled, Deltex, Dishevelled), and proteins acting within the nucleus (Hairless, EMB-5, Strawberry notch).<ref name="PMID9892565">As reviewed by <pubmed>9892565</pubmed></ref><br />
<br />
In ''Drosophila melanogaster'', it has been seen that ''fringe'' is able to affect the ability of Notch to be activated by the Serrate and Delta ligands. Specifically in the ''Drosophila'' wing, it was observed that Serrate did not interact with Notch in specific areas due to the action of ''fringe''<ref><pubmed>9247339</pubmed></ref>. Fringe is not required for initial Notch signalling, but is thought to be important for signalling processes when Notch activation occurs along the borders between distinct cell populations. Research suggests that Fringe specifically affects the binding between Notch and its ligands, rather than an activation step separate or subsequent to ligand binding. The ''brainiac'' and ''egghead'' genes are thought to either influence the production of a Notch ligand or act as substitute ligands themselves.<ref name="PMID9892565"/><br />
<br><br><br />
<br />
====Examples of Proteins Involved in Interaction with the Notch Intracellular Domain <small>(adapted from Table 3<ref name="PMID21828089"/>)</small>====<br />
{| class="pretty table"<br />
|-bgcolor="A3BFB1" <br />
| '''Protein'''<br />
| '''Interaction with NICD'''<br />
|-bgcolor="F5FFFA"<br />
| Adenamatous polyposis coli (Apc)<br />
| Controls Notch trafficking<br />
|-<br />
| Cyclin-dependant kinase 8 (CDK8)<br />
| Phosphorylates NICD to make it a substrate for ubiquitylation and degradation<br />
|-bgcolor="F5FFFA"<br />
| CBF1, Su(H) and LAG-1/Recombination signal binding protein for immunoglobulin kappa J region (CSL/RBP-J)<br />
| Main canonical transcriptional co-factor for NICD<br />
|-<br />
| Cyclin C (CycC)<br />
| Targets NICD for phosphorylation to make it a substrate for ubiquitylation and degradation<br />
|-bgcolor="F5FFFA"<br />
| Dishevelled (Dsh/Dvl)<br />
| Controls ligand-independent Notch trafficking; inhibits canonical Notch signalling<br />
|-<br />
| Deltex-1-4 (Dtx1-4)<br />
| Controls Notch ubiquitylation, processing, and internalisation<br />
|-bgcolor="F5FFFA"<br />
| Itchy, E3 ubiquitin protein ligase (Itch)<br />
| Promotes ubiquitylation of NICD<br />
|-<br />
| Mastermind-like 1/2 (Maml1/2)<br />
| Co-activator for NICD/CSL<br />
|-bgcolor="F5FFFA"<br />
| Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-ϰb)<br />
| NICD blocks NF-ϰb transcription of NF-ϰb target genes through binding to p50/cRel<br>NICD enhances NF-ϰb transcription of target genes by retaining NF-ϰb in the nucleus<br />
|-<br />
| Numb homolog (Numb)<br />
| Suppresses Notch signaling by recruiting E3 ubiquitin ligases to ubiquitylate Notch<br>Controls Notch trafficking during asymmetric cell division<br />
|-bgcolor="F5FFFA"<br />
| Smad family members (SMAD)<br />
| Smads enhance Notch signalling; Notch fine-tunes signalling through Smads<br />
|}<br />
<br><br />
<br />
===Roles in Embryonic Development===<br />
The phylogenetically conserved Notch signalling pathway plays a crucial role in the development of multiple organ systems, and is a major regulator of stem cell fate. It is responsible for the regulation of the transcription of a number of signalling molecules, such as ''MyoD'', ''Mash1'' and ''GATA2'', which are genes controlling the fate of myogenic, neurogenic and haematopoietic stem cells, respectively. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> The following subsections will further elucidate the vital roles of Notch signalling during normal embryonic development. If you would like to better understand human embryonic development before reading this section, [https://embryology.med.unsw.edu.au/embryology/index.php/Embryonic_Development| this page] serves as a great resource. <br />
<br><br><br />
<br />
====Cardiovascular====<br />
<br />
If you would like to generally learn about and become familiar with cardiac development in the embryo before reading this section, click [https://embryology.med.unsw.edu.au/embryology/index.php/ANAT2341_Lab_11_-_Heart here]!<br />
<br />
'''Cardiomyocyte Specification and Differentiation'''<br />
<br />
Expression during the appropriate window of the timeline of embryogenesis of Notch receptors, ligands and downstream effector molecules elucidates a role for the Notch pathway in the earliest stages of cardiac development. It has been found to restrict the expression of specific cardiogenic genes in a spatiotemporal manner and regulate cardiac field specification as early as during gastrulation. <ref name=PMID19580804><pubmed>19580804</pubmed></ref> Interestingly, Notch has been found to play both suppressive and promoting roles in cardiogenesis.<br />
<br />
For example, it has been shown that Notch suppresses cardiomyocyte cell fate specification during early cardiogenesis. This has been demonstrated through studies such as that carried out by Rones and colleagues (2000), which used activation and inhibition of Notch signaling in Xenopus. <ref name=PMID10934030><pubmed>10934030</pubmed></ref><br />
<br />
On the other hand, studies such as that by Boni et al. (2008) have found that Notch signalling may also promote myogenesis from cardiac progenitor cells. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> Cardiogenesis has also been promoted by downregulating Notch-1 activity in stem cells of embryos (Nemir et al., 2006).<ref name=PMID16690879><pubmed>16690879</pubmed></ref><br />
<br />
Despite the understanding that Notch signalling is crucial to embryonic myogenesis, the exact molecular mechanism remains elusive. Research by Buas and colleagues (2010) has explored such mechanisms by studying the Notch target, Hey1, which is known to suppress myogenic differentiation. They concluded that this inhibitory function of Hey1 is primarily mediated through binding near to myogenin and Mef2C promoters, which leads to cessation of target gene expression. <ref name=PMID19917614><pubmed>19917614</pubmed></ref><br />
<br />
[[File:Notch CVS simple diagram.png|thumb|500px|right|alt=Simplified Scheme of the Roles of Notch in Cardiac Development|'''Simplified Scheme of the Roles of Notch in Cardiac Development.''' Notch has been found to restrict the expression of specific cardiogenic genes in a spatiotemporal manner and regulate cardiac field specification early in development. Further after cardiac differentiation, Notch influences development of the AVC (atrioventricular canal), cardiac valves, ventricular trabeculae and the cardiac outflow tract. (This student-drawn image is based upon Figure 2 in the 2014 review by Zhou and Liu: [https://www.ncbi.nlm.nih.gov/pubmed/24345875 ''Role of Notch signaling in the mammalian heart.'']<ref name=PMID24345875><pubmed>24345875</pubmed></ref>)]]<br />
<br />
'''Development of the Atrioventricular Canal'''<br />
<br />
A study by Rutenberg et al. (2006) and another by Kokubo et al. (2007) implicate a role for Notch signaling in the region between the atria and the ventricles of the heart (the atrioventricular canal, or AVC).<ref name=PMID17021042><pubmed>17021042</pubmed></ref> <ref name=PMID17259303><pubmed>17259303</pubmed></ref> They used chicken and mouse models, respectively, to show that other signalling factors, ''Bmp2'' and ''Tbx2'', are restricted to the AVC region by Notch signalling during development. <br />
<br />
Furthermore, Watanabe and colleagues (2006) showed that deletion of Notch targets increases ''Bmp2'' expression and expansion of the AVC tissue, however other, non-Notch restrictive factors involved in AVC development are likely to exist.<ref name=PMID16554359><pubmed>16554359</pubmed></ref> <br />
<br />
'''Heart Valve Development'''<br />
<br />
In order for the heart valve to properly form in the embryo, endocardial to mesenchymal transformation (EMT) must occur. The Notch pathway, alongside Wnt and Bmp, has been found to regulate the process of EMT, defects in which can lead to congenital heart valve disease. Interestingly, Timmerman and colleagues (2004) demonstrated that this role of Notch may also promote oncogenic transformation. This team also showed that embryos exhibited abortive endocardial EMT if they were deficient in Notch signalling components in vivo and in vitro. <ref name=PMID14701881><pubmed>14701881</pubmed></ref> <br />
<br />
A more recent paper by Wang et al. (2013) further explored the underlying signalling processes and interrelationships of molecules that impact EMT. They found that Jagged1-Notch1 signalling in cells of the endocardium potentiates expression of Wnt4, which in turn carries out paracrine action on adjacent AVC tissue to upregulate Bmp2 expression and thus signal EMT. <ref name=PMID23560082><pubmed>23560082</pubmed></ref><br />
<br />
'''Trabeculation'''<br />
<br />
Trabeculation is the initial process of ventricular chamber development that forms a series of cardiomyocyte projections within the lumens of the ventricles of the heart (called trabeculae). Grego-Bessa and colleagues (2007) addressed the roles Notch plays in trabeculation through ''RBPJk'' (the gene product of which interacts with Notch) and ''Notch1'' gene manipulation. Mutants of these two genes showed perturbed expression and signalling of ''EphrinB2'', ''NRG1'' and ''BMP10'', alongside reduced proliferation of myocardiocytes. This research ultimately suggested that ''EphrinB2'' is a direct target of Notch in the endocardium that simultaneously requires the Notch-dependent action of BMP10 and NRG1 in order for ventricular myocardium proliferation and differentiation to occur normally. <ref name=PMID17336907><pubmed>17336907</pubmed></ref> Furthermore, the important process of trabeculation has recently been shown to be controlled by sequential Notch activation by an investigation by D’Amato et al. (2015). <ref name=PMID26641715><pubmed>26641715</pubmed></ref><br />
<br />
'''Development of the Outflow Tract'''<br />
<br />
About one third of congenital heart defects include malformations in the outflow tract which include the aorta, pulmonary arteries, aortic arch and ductus arteriosus. During cardiogenesis, neural crest cells interact with second heart field myocardium and endocardial mesenchyme. <ref><pubmed>20201902</pubmed></ref> <br />
Studies involving neurogenesis demonstrated the sensitivity of Notch signaling to temporal and spatial cues and showed the early Notch signaling initially controls the number of cells with a neurogenic fate and later dictates the lineage decision of neural versus glial cell fate. <ref><pubmed>16429119</pubmed></ref><br />
Neural crest precursors for ideal patterning of the outflow tract are required in the Notch signaling pathway. The use of a dominant negative form of a master mind like protein (MAML) which has shown to be a pan Notch inhibitor in neural crest cells inactivates Notch signaling. This results in congenital heart defects like pulmonary artery stenosis and aortic arch patterning defects associated with defects in smooth muscle formation. <ref><pubmed> 17273555 </pubmed></ref><br />
Part of the phenotype in defective neural crest cells is attributed to loss of Notch2 signalling as Notch2 inactivation in these cells produces small caliber aortas and pulmonary arteries because of defects in smooth muscle. <ref><pubmed> 18330927 </pubmed></ref><br />
Jagged1 is the ligand involved which signals to Notch on neural crest cell surfaces to induce vascular smooth muscle cell differentiation. <ref><pubmed> 18245384 </pubmed></ref><br />
Mutations in both JAGGED1 and NOTCH2 genes have been known to cause Alagille syndrome, further substantiating the importance of this pathway in proper formation of the outflow tract. <ref><pubmed> 16575836 </pubmed></ref><br />
<br />
Another study by Garg stresses the importance of Notch signaling in the outflow tract region. NOTCH1 mutations were seen in patients with aortic stenosis. Aortic stenosis results from the calcification of the aortic valve and is quite common in adults. However, in children, this may result in failure of the left ventricle to develop properly. NOTCH1 haploinsufficiency is also linked to early calcification and bicuspid aortic valve disease. This could be due to an early induction of Runx2 through the HRT genes.<br />
<ref><pubmed> 16025100 </pubmed></ref><br />
<br />
<br><br><br />
<br />
====Central Nervous System====<br />
<br />
If you would like to generally learn about and become familiar with neural development in the embryo before reading this section, click [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Neural_Development here]!<br />
<br />
[[File:Notch CNS simple diagram.png|thumb|450px|right|alt=Simplified Diagram of Roles of Notch in Neuronal Differentiation|'''Simplified Diagram of Roles of Notch in Neuronal Differentiation'''. Notch influences the differentiation of embryonic stem cells into neural cells via signalling with RBP (recombining binding protein), cyclin D1 and Hes1. (This student-drawn image is based upon Figure 1 from Chuang, Tung and Lin's 2015 review: [https://www.ncbi.nlm.nih.gov/pubmed/25815127 ''Neural differentiation from embryonic stem cells in vitro: An overview of the signaling pathways'']<ref name="PMID25815127"><pubmed>25815127</pubmed></ref>)]]<br />
'''Early Neural Differentiation'''<br />
<br />
Notch plays a major role in promoting neural commitment of cells. Lowell and colleagues (2011) used genetic manipulation to discover that the phenotype of stem cells is not affected by constitutively activated Notch in mouse embryonic stem cells (mESCs), however, interfering with Notch signalling -for example by pharmacological means- did impede neural fate determination. This role required Notch signalling via fibroblast growth factor (FGF) receptors. Furthermore, the conservation of the Notch signalling pathway within pluripotent stem cells is implied due to the existence of Notch ligands in stromal cells in human embryonic stem cells (hESCs) that induce neural differentiation. <ref name=PMID16594731><pubmed>16594731</pubmed></ref><br />
<br />
Das and colleagues (2010) manipulated Notch protein levels during specific stages of neural differentiation and found that if Notch signalling pathways were activated during day 3 of neural development for 6 hours, cell proliferation was dramatically enhanced. This was attributed to the induction by Notch of cyclin D1 expression. Without Notch signalling during neural development, there was reduced cyclin D1 levels. Manipulation of mESCs to express a dominant negative form of cyclin D1 resulted in abrogation of cell proliferation stimulated by Notch. Overall these results imply a temporally-specific role for Notch in CNS development, and that it requires cyclin D1 as a signalling molecule.<ref name=PMID20887720><pubmed>20887720</pubmed></ref><br />
<br />
Hes1 has also been shown to play a Notch-mediated role in neural progenitor maintenance, which is essential for proper development since cells need to proliferate only during specific periods in the embryo for the correct number, cell type and function to result. Shimojo, Ohtsuka and Kageyama (2008) used real time imaging in mice to show that Notch induces oscillatory expression of ''Hes1'' and other Notch target genes to maintain the complex temporal organisation of events in neural development. They concluded that further research could elucidate more about Hes1 oscillations in regards to neural progenitor maintenance, proliferation and differentiation <ref name=PMID18400163><pubmed>18400163</pubmed></ref>.<br />
<br />
Lastly, as well as influencing neural progenitor differentiation, it has been found that Notch also impacts the development and maintenance of polarised neural structures in the embryo. This was concluded from a knockout study in mice that elucidated a role for RBP (recombining binding protein), downstream of Notch, in modulating neural differentiation and maintaining rosette structure (an experimental ''in vitro'' correlate used for neural tube development) <ref name=PMID23675446><pubmed>23675446</pubmed></ref>. The researchers concluded that RBP knockouts lacked canonical Notch signalling and as a result showed multiple neurulation defects.<br />
<br><br><br />
<br />
====Other Systems====<br />
<br />
As aforementioned, Notch plays a wide array of roles in embryonic development, the follow table summarises these roles by each organ system:<br />
<br />
<big>Summary Table of Examples of Notch Signalling in Developmental Processes</big> <small>(adapted from Table 1<ref name="PMID21828089">As reviewed by <pubmed>21828089</pubmed></ref>)</small><br />
{| class="pretty table"<br />
|-bgcolor="CEDFF2"<br />
| '''Organ/Tissue'''<br />
| '''Processes regulated by Notch'''<br />
|-bgcolor="F5FAFF" <br />
| Brain<br />
| Controls the balance between gliogenesis and neurogenesis; stem cell maintenance<ref><pubmed>21262462</pubmed></ref><ref>As reviewed by <pubmed>20816397</pubmed></ref>; organisation and maintenance of polarity during early development<ref name="PMID23675446"/><br />
|-<br />
| Craniofacial structures<br />
| Palate morphogenesis: loss of Notch signalling results in cleft palate, fusion of the tongue with the palatal shelves, and other craniofacial defects; also involved in tooth development<br />
|-bgcolor="F5FAFF"<br />
| Ear<br />
| Defines the presumptive sensory epithelium; determines hair cell and supporting cell fates<br />
|-<br />
| Esophagus<br />
| Regulates esophageal epithelial homeostasis<br />
|-bgcolor="F5FAFF"<br />
| Heart<br />
| Cardiac patterning, cardiomyocyte differentiation, valve development, ventricular trabeculation, outflow tract development<br />
|-<br />
| Intestine<br />
| Controls proliferation and differentiation, including absorptive vs. secretory cell fates<br />
|-bgcolor="F5FAFF"<br />
| Limbs<br />
| Apical ectodermal ridge (AER) formation and digit morphogenesis, especially regulation of apoptosis<br />
|-<br />
| Lungs<br />
| Lateral inhibition between tracheal cells prevents extra cells from assuming the lead position during tracheal branching morphogenesis<br />
|-bgcolor="F5FAFF"<br />
| Neural crest<br />
| Controls patterning of neural crest precursors for the outflow tract region of the heart; regulates the transition from Schwann cell precursor to Schwann cell, controls Schwann cell proliferation and inhibits myelination; controls melanocyte stem cell maintenance<br />
|-<br />
| Pancreas<br />
| Specifies endocrine cell differentiation through lateral inhibition: endocrine lineage cells inhibit endocrine differentiation of their neighboring cells; maintains pancreatic endocrine precursor cells, inhibits terminal acinar cell differentiation; controls pancreatic epithelium branching and bud size<br />
|-bgcolor="F5FAFF"<br />
| Skin<br />
| Regulates cell adhesion, control of proliferation, hair follicle or feather papillae differentiation and homeostasis<br />
|-<br />
| Thyroid<br />
| Regulates the numbers of thyrocyte and C-cell progenitors and regulates differentiation and endocrine function of thyrocytes and C-cells<ref><pubmed>21364918</pubmed></ref><br />
|-bgcolor="F5FAFF"<br />
| Vasculature<br />
| Regulates arteriovenous specification and differentiation in endothelial cells and vascular smooth muscle cells; regulates blood vessel sprouting and branching<br />
|}<br />
<br />
====Quiz Your Notch-Knowledge on Embryonic Development!====<br />
<br />
<quiz display=simple><br />
<br />
{ In the development of which organ does Notch exert lateral inhibition to differentiate endocrine cells?<br />
|type="()"}<br />
- &nbsp; The heart<br />
- &nbsp; The central nervous system<br />
- &nbsp; The skin<br />
+ &nbsp; The pancreas<br />
|| Remember, Notch signals endocrine lineage cells of the developing pancreas to inhibit endocrine differentiation of their neighbouring cells, known as lateral inhibition. Notch plays various roles in the heart, central nervous system and skin, but not in this way. <br />
</quiz><br />
<br><br />
<br />
===Roles in Animal Development===<br />
The Notch signalling pathway doesn't just play a significant role in human development, but also affects events such as neurogenesis and myogenesis in some animals (thus why these animals are often used as models for human development in research!). Read below for information on some of these roles for Notch.<br />
<br><br><br />
<br />
[[File:Notch animals.png|thumb|450px|right|alt=Animals Whose Developmental Processes are Affected by Notch.|'''Animals Whose Developmental Processes are Affected by Notch.''' This is a simplified representation of a few examples of the animals (Drosophila flies<ref name=PMID21447553><pubmed>21447553</pubmed></ref>, C. elegans<ref name=PMID18599512><pubmed>18599512</pubmed></ref>, and the zebrafish<ref><pubmed>23840804</pubmed></ref>) in which development is influenced by the Notch signalling pathway, and their scientific names.]]<br />
<br />
====''Drosophila melanogaster''====<br />
<br />
'''(The Fly)'''<br />
<br />
Unlike the four Notch paralogs in humans, only one Notch homolog is present in ''Drosophila''.<ref name="Introduction to Notch Signalling"/><br />
<br />
Both canonical and non-canonical Notch signalling are involved in the structural and physiological responses and functional plasticity of olfactory receptor neurons in reaction to prolonged odour exposure.<ref><pubmed>26986723</pubmed></ref><ref><pubmed>26011623</pubmed></ref> Research has also shown that Notch is crucial for the formation of longitudinal connections in the Drosophila CNS. Kuzina, Song, and Giniger (2011) created temperature-sensitive mutations of Notch genes that prevented the development of mature longitudinal axon tracts. Additionally, it was found that the Notch phenotype appears at the earliest stages of the development of longitudinal connections in the CNS by observing early stage 13 embryos.<ref name=PMID21447553><pubmed>21447553</pubmed></ref><br />
<br><br><br />
<br />
====''Caenorhabditis elegans''====<br />
<br />
'''(The Worm)'''<br />
<br />
The Notch pathway in ''C. elegans'' occurs throughout development in populations of equipotent cells for neuronal function in postmitotic differentiated neurons. In these postmitotic neurons, there is a specialised post-embryonic development stage knows as 'dauer'. The Notch pathway is activated when cell signalling downstream of the developmental decision enter dauer. The Notch receptor glp-1 and the ligand lag-2 are expressed in the dauer stage and aid in maintaining this stage. Another Notch receptor, lin-12, functions upstream of insulin signalling components to promote conditions for growth and enhance dauer recovery. <ref name=PMID18599512><pubmed>18599512</pubmed></ref><br />
<br><br><br />
<br />
====''Danio rerio''====<br />
<br />
'''(The Zebrafish)'''<br />
<br />
The expression of Notch in the myogenic region and apical ectodermal ridge (AER) of the developing zebrafish fin is similar to what has been observed in developing chicken and mouse limbs, which shows how highly conserved the role of Notch signalling is in the development of appendages in vertebrates. During zebrafish embryogenesis, the timing and positioning of fin formation are dependent on Notch signalling. Notch is also involved in the actual processes of fin formation, such as AER signalling, chondrogenic differentiation, and myogenesis. In zebrafish embryos with defective Notch signalling, it was observed that the skeletal muscle fibres were thin and fragmented and the structure of the sarcomeres was significantly compromised. <ref name="PMID23840804"><pubmed>23840804</pubmed></ref><br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Expand this for an image from this research study</big><br />
|-<br />
|[[File:Abnormal pectoral fins are formed in Notch signalling disrupted larvae.jpg|thumb|450px|right|alt=Abnormal pectoral fins are formed in Notch signalling disrupted larvae|'''Abnormal pectoral fins are formed in Notch signalling disrupted larvae.''' (A–F) Live pictures of 5 dpf larvae. (A’) A pectoral fin from a sibling embryo showing the cartilaginous endoskeletal disc with individualized cells surrounded by thin matrix deposits, the fin fold and the chleitrum (n = 17) (E, E’). A similar pectoral fin was found in a DMSO-treated embryo (n = 9). Pectoral fins of Notch signalling disrupted embryos such as mibta52b (n = 18) (B, B’), jagged2 (n = 10) (C, C’) and Su(H)1+2 (n = 12) (D, D’) morphants and DAPT-treated embryos (n = 10) (F, F’) showing disorganized endoskeletal disc cells. cl, chleitrum; ed, endoskeletal disc; ff, fin fold.<ref name="PMID23840804"/>]]<br />
|}<br />
<br><br><br />
<br />
====Quiz Your Notch-Knowledge on Animal Development!====<br />
<br />
<quiz display=simple><br />
<br />
{In which animal (as described in this section) has it been shown that defective notch signalling leads to thinning and fragmentation of skeletal muscle fibres?<br />
|type="()"}<br />
- &nbsp; Drosophila melanogaster<br />
- &nbsp; I don't know!<br />
- &nbsp; Caenorhabditis elegans<br />
+ &nbsp; Danio rerio<br />
|| Remember, it was observed in one study that the skeletal muscle fibres of zebrafish (Danio rerio) were thin and fragmented and the structure of their sarcomeres were significantly compromised.<ref><pubmed>23840804</pubmed></ref> <br />
</quiz><br />
<br />
===Summary of Functions of Proteins Involved in Notch Signalling <small>(adapted from Table 1<ref name="PMID17761886"><pubmed>17761886</pubmed></ref>)</small>===<br />
{| class="pretty table"<br />
|-bgcolor="a3bfb1"<br />
| '''Mammals'''<br />
| '''''Drosophila'''''<br />
| '''''C.elegans'''''<br />
| '''Function'''<br />
|-bgcolor="F5FFFA" <br />
| Notch 1-4<br />
| Notch<br />
| Lin-12, Glp-1<br />
| Single transmembrane receptor and transcription factor<br />
|-<br />
| Delta 1, Delta3-4, Jagged1-2<br />
| Delta, Serrate<br />
| APX-1, LAG-2, ARG-1, DSL-1<br />
| Single transmembrane ligands of the Notch receptor<br />
|-bgcolor="F5FFFA" <br />
| CBF1/RBPJK<br>Mastermind1-3<br />
| Su(H)<br>Mastermind<br />
| Lag-1<br>Lag-3<br />
| DNA-binding transcription factor<br>Transcriptional co-activator<br />
|-<br />
| Lunatic, manic, and radical Fringe<br />
| Fringe<br />
|<br />
| Modifies both Notch and its ligands<br />
|-bgcolor="F5FFFA" <br />
| ADAM10, ADAM17<br />
| Kuzbanian, Kuzbanian-like, TACE<br />
| SUP-17, ADM-4<br />
| Metalloproteases targeting S2 Notch cleavage sites<br />
|-<br />
| Presenilin 1-2, nicastrin, APH1, PEN2<br />
| Presenilin, nicastrin, APH1, PEN2<br />
| SEL-12, APH-1, APH-2, PEN2<br />
| Proteins of the γ-secretase complex, which targets Notch S3 and S4 cleavage sites<br />
|-bgcolor="F5FFFA" <br />
| Mind bomb, skeletrophin, neuralized 1-2<br />
| Mind bomb 1-2, neuralized<br />
| Y47D3A.22<br />
| E3 ubiquitin-protein ligases that targets Delta and Jagged/Serrate and regulate their endocytosis<br />
|}<br />
<br><br />
<br />
===Abnormalities in Notch Signalling===<br />
Mutations in Notch genes and hence defects in Notch signalling have been implicated in the pathogenesis of several inherited diseases in humans.<ref name="PMID23729744">As reviewed by <pubmed>23729744</pubmed></ref><ref name="PMID22306179">As reviewed by <pubmed>22306179</pubmed></ref> The diseases listed in this summary table are only a few examples and are described in more detail below.<br />
<br><br />
<br />
{| class="pretty table"<br />
|-bgcolor="CEDFF2" <br />
| '''Disease'''<br />
| '''Gene'''<br />
| '''Phenotype'''<br />
|-bgcolor="F5FAFF" <br />
| Alagille syndrome ([http://omim.org/entry/118450 OMIM118450], [http://omim.org/entry/610205 OMIM610205])<br />
| ''JAG1'', ''NOTCH2''<br />
| Developmental abnormalities of the heart, liver, eye, and skeleton. Neonatal jaundice and cholestasis are early symptoms.<br />
|-<br />
| CADASIL ([http://omim.org/entry/125310 OMIM125310])<br />
| ''NOTCH3''<br />
| Autosomal vascular disorders linked to ischemic strokes, dementia, and premature death.<br />
|-bgcolor="F5FAFF"<br />
| T-cell acute lymphoblastic leukaemia ([http://omim.org/entry/613065 OMIM613065])<br />
| ''NOTCH1'' (mutation in heterodimerization domain or PEST domain)<br />
| Tumour derived from T-cell progenitors. Symptoms include anaemia and enlargement of lymph nodes in the liver and/or spleen.<br />
|-<br />
| Spondylocostal dysostosis ([http://omim.org/entry/122600 OMIM122600])<br />
| ''DLL3'', Lunatic fringe<br />
| Vertebral segmentation defects as well as rib abnormalities.<br />
|}<br />
<br />
====Alagille Syndrome====<br />
Alagille syndrome (AGS) is an autosomal dominant, multisystem disorder that mainly affects the liver, heart, and kidney. Diagnostic characteristics of the disease include liver disease, cardiac disease, vertebral defects, eye conditions, and facial features, as well as renal and vascular abnormalities.<ref>As reviewed by <pubmed>26548814</pubmed></ref> Two variants of AGS, type 1 and type 2, have been identified, and each is related to different defects in the Notch pathway. In clinically diagnosed cases of AGS type 1 (which accounts for approximately 97% of all cases of AGS), a mutation in the gene encoding the Notch ligand Jagged1 (Jag1) has been identified as a contributing factor.<ref>As reviewed by <pubmed>11745040</pubmed></ref> In the much rarer AGS type 2, a mutation in the NOTCH2 gene has been implicated in the manifestation of AGS. The mechanisms by which mutations in JAG1 and NOTCH2 lead to pathogenesis of AGS are not well understood, but it is known that normal Notch signalling is important in angiogenesis. Therefore, it is thought that abnormal JAG1 or NOTCH2 will cause disruptions to the pathway that leads to the vascular disorders present in AGS. This is also evidenced by research that JAG1 knockout mice suffer premature death due to vascular defects.<ref>As reviewed by <pubmed>21934706</pubmed></ref> It is possible that AGS caused by a mutation in NOTCH2 alone will lead to a different presentation than AGS patients with mutated JAG1; however, this is still undergoing further research. It is also unclear why AGS type 2 occurs at a significantly lower incidence than AGS type 1.<ref><pubmed>16773578</pubmed></ref><br />
<br><br><br />
<br />
====Spondylocostal Dysostosis====<br />
Spondylocostal Dysostosis (SD) is a collective term for conditions characterised by anomalies relating to rib and spine. The vertebrae are fused and shaped abnormally which can result in scoliosis. Similarly, the ribs may also be fused together or in some cases completely missing. As a result, people with this condition have short trunk dwarfism where their bodies are short in stature but have normal length limbs. Genetic changes are known to cause SD. SD Type 1 is the most prevalent form of this disease which is caused by the mutation in the delta like canonical Notch ligand 3 (DLL3 gene).<ref><pubmed>10742114</pubmed></ref> DLL3 provides the information for making a protein that regulates the Notch signalling pathway. The DLL3 protein in conjunction with the Notch pathway is primarily responsible for preventing the fusion of future vertebrae in a process known as somite segmentation.<ref><pubmed>11236715</pubmed></ref> An interruption in the Notch pathway inhibits the somite segmentation resulting in abnormalities relating to the ribs and spine as seen in SD. 25 percent of SD arise from mutations in the identified genes and further research suggest that other genes involved in the Notch signalling pathway may also be related to SD.<br />
<br><br><br />
<br />
====Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)====<br />
CADASIL is an autosomal-dominant disease of the small to medium-sized arteries, mainly in the brain, that leads to dementia and disability in mid-life. The symptoms, age of onset, and prognosis are variable. Distinguishing symptoms include subcortical ischemic events (60-80% of cases), cognitive impairment (60% of late stage disease), migraines (30-40%), mood disturbances (30%), and apathy (40%).<ref name="PMID21045164"><pubmed>21045164</pubmed></ref><ref name="PMID20301673"><pubmed>20301673</pubmed></ref> Approximately 5-10% of CADASIL patients also experience seizures. The mean age of onset is 45 years of age and the disease duration is between 10–40 years. More than 95% of CADASIL cases present with pathogenic mutations in NOTCH3 (located on chromosome 19p13), specifically the epidermal growth factor-like repeat domain.<ref name="PMID20301673"/><ref><pubmed>24579972</pubmed></ref> The NOTCH3 gene is involved in the normal development of blood vessels in both fetal and adult brains. In adults, NOTCH3 is expressed in the smooth muscle cells of arteries.<ref name="PMID21045164"/> There is currently no effective treatment available for CADASIL.<br />
<br><br><br />
<br />
====Congenital Heart Defects====<br />
<br />
'''Aortic Valve Disease'''<br />
<br />
[[File:Aortic valve disease.jpg|thumb|450px|right|alt=Loss of NOTCH1 expression in proximity to calcific nodules in human aortic valves|'''Loss of NOTCH1 expression in proximity to calcific nodules in human aortic valves.''' (A) Representative sections from control (A,B) and diseased (C-F) aortic valve cusps. (B) is high magnification image of boxed area in (A) and (D,E) are higher magnification of region in (C) while image in (F) shows another calcified aortic valve. Expression of Notch1 intracellular domain (NICD) is found in the thickened fibrosa of diseased aortic valve (C,E) as compared to the acellular fibrosa of control valves (A,B). However, there is significant loss of NICD expression in cells residing adjacent to calcific nodules (D,F). The fibrosa is oriented upward in all panels, and scale bars equal 100 microns (B,D,E,F are at same magnification). Brown signal represents NICD expression while nuclei are counterstained in blue.<ref name="PMID22110751"><pubmed>22110751</pubmed></ref>]]<br />
<br />
Calcification of the aortic valve is a leading cause of adult heart disease. Mutations in NOTCH1 have been found to cause various aortic valve abnormalities, including the development of a bicuspid aortic valve (as opposed to tricuspid) and valve calcification.<br />
<br />
&emsp;&emsp;A study by Garg et al. (2005) looked at mouse embryos and the expression of ''Notch1'' during development. It was found that during normal embryonic development, ''Notch1'' was abundantly expressed in the outflow tract mesenchyme (which develops into the heart valves) and the endocardium, as well as in the endothelial layer and mesenchyme of the aortic valve leaflets at the time of arterial trunk septation. Abnormal ''Notch1'' led to the death of mice from vascular endothelial defects. Garg et al. then investigated whether NOTCH1 was involved in calcium deposition and therefore valve calcification. This is thought to be due to differentiation of valve cells into osteoblast-like cells. This leads to the upregulation of osteopontin, osteocalcin, and other osteoblast-specific genes, which is normally regulated by the transcription factor Runx2. Runx2 is known to be upregulated in animal models of valve calcification. Garg et al. found that Notch1 was capable of repressing Runx2 activation. Heart tissue and vasculature are normally abundant with the hairy-related transcriptional repressors Hrt1 and Hrt2 (also called Hey1 and Hey2), which are normally activated by Notch and are key mediators of the Notch pathway. Hrt1 and Hrt2 were both expressed in the endothelium of the mice aortic valve leaflets, the endocardium, and the vascular endothelium. They were found to inhibit the activation of osteoblast-specific genes by Runx2. It was thought that Hrt proteins can repress Runx2 by physical interaction as well as mediate Notch1 repression of Runx2. Therefore, a defect in Notch will cause upregulation of Runx2, due to the lack of repressor activity by Notch itself and the activation of the repressors Hrt1 and Hrt2. This leads to the expression of osteoblast genes that results in the differentiation of valvular cells into osteoblast-like cells and ultimately causes aortic valve calficiation.<ref><pubmed>16025100</pubmed></ref><br />
<br />
The picture to the right is a histological image of aortic valve disease from a study performed in rats investigating molecular changes that occurred when Notch signalling was suppressed in the aortic valve.<ref name="PMID22110751"/><br />
<br><br><br />
<br />
====Tumourigenesis====<br />
Notch has been shown to be involved in cancer development and can act as both an oncogene and a tumour suppressor gene.<ref>As reviewed by <pubmed>14570040</pubmed></ref><ref name="PMID23729744"/> Defective Notch signalling has been implicated in the pathogenesis of several human cancers, such as acute myelogenous leukemia (overexpression of Jagged1 and Notch1), multiple myeloma (overexpression of Jagged1/2 and Notch1/2), and B-cell–derived Hodgkin lymphoma (overexpression of Jagged1 and Notch1).<ref name="PMID16291593">As reviewed by <pubmed>16291593</pubmed></ref><br />
<br />
Elevated levels of Notch ligand proteins and/or mRNA have been observed in several cancers. Upregulated Jagged1 mRNA has been seen in human pancreatic cancer; Jagged1 protein overexpression has also been studied in prostate, cervix, and brain cancers. Cervical cancers have shown upregulated Jagged2 mRNA. Additionally, elevated Dll1 mRNA has been observed in cervical cancers, as well as in human brain cancers at both Dll1 mRNA and protein levels. Additionally, defective Notch receptor expression has been implicated in cancer as well. For example, elevated Notch1 protein expression has been found in cervical, colon, lung, pancreas, skin, and brain cancers. Protein overexpression of Notch3 and Notch4 has also been seen in malignant melanoma and pancreatic cancer.<ref name="PMID16291593"/><br />
<br />
Interestingly, research has shown that Notch signalling can also have a tumour-suppressive effect. Studies have indicated that Notch signalling can inhibit proliferation and even stimulate apoptosis in malignant B-cells. Furthermore, the Notch1 intracellular domain has also shown the ability to induce growth arrest and apoptosis in Hodgkin lymphoma and multiple myeloma cells.<ref name="PMID16291593"/><br />
<br><br><br />
<br />
'''T-Cell Acute Lymphoblastic Leukaemia'''<br><br />
T-cell acute lymphoblastic leukaemia (T-ALL) is an example of how abnormal Notch signalling can lead to the development of cancer. T-ALL is an aggressive childhood cancer of the immune system's T-cells. The NOTCH1 gene encodes the Notch1 receptor, which is involved in the determination of pluripotent cell progenitors to T-cells and the organisation of these cells in the developing thymus. Activating mutations in the extracellular domain and/or the C-terminal PEST domain of Notch1 have been identified in more than half of all cases of T-ALL.<ref><pubmed>15472075</pubmed></ref><br />
<br><br><br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Other Examples of Roles of Notch in Cancer <small>(adapted from ''Notch in disease''<ref name="PMID23729744"/>)</small><br />
|-<br />
|-bgcolor="a3bfb1"<br />
| '''Gene'''<br />
| '''Role of Notch'''<br />
| '''Disease'''<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br>''NOTCH2''<br />
| Oncogene<br>Tumour suppressor<br />
| Pancreatic ductal adenocarcinoma<br />
|-<br />
| ''NCSTN''<br>''MAML1''<br>''APH1A''<br>''NOTCH2''<br />
| Tumour suppressor<br />
| Chronic myelomonocytic leukaemia<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br />
| Oncogene<br />
| Chronic lymphocytic leukaemia<br />
|-<br />
| Activated NOTCH<br />
| Tumour suppressor<br />
| Hepatocellular carcinoma<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br>''NOTCH2''<br>''NOTCH3''<br />
| Tumour suppressor<br />
| Head and neck squamous cell carcinoma<br />
|-<br />
| NOTCH<br />
| Tumour suppressor<br />
| B-cell acute lymphoblastic leukaemia<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br />
| Oncogene<br />
| Non-small-cell lung cancer<br />
|-<br />
| ''NOTCH1''<br />
| Oncogene<br />
| T-cell acute lymphoblastic leukaemia<br />
|}<br />
<br><br />
<br />
====Quiz Your Notch-Knowledge on Abnormalities in Notch Signalling!====<br />
<br />
<quiz display=simple><br />
{ What is the name for the collection of rib and spine abnormalities that result from interruption in the Notch pathway that leads to inhibition of somite segmentation in the embryo?<br />
|type="()"}<br />
- &nbsp; Alagille Syndrome<br />
- &nbsp; T-cell acute lymphoblastic leukaemia<br />
+ &nbsp; Spondylocostal Dysostosis<br />
- &nbsp; CADASIL<br />
|| Remember, Spondylocostal Dysostosis is a collective term for conditions characterised by anomalies relating to rib and spine. Genetic changes lead to an interruption in the Notch pathway that inhibits the somite segmentation resulting in abnormalities relating to the ribs and spine. Alagille syndrome is an autosomal dominant, multisystem disorder that mainly affects the liver, heart, and kidney. T-cell acute lymphoblastic leukaemia is an aggressive childhood cancer of the immune system's T-cells. CADASIL is an autosomal-dominant disease of the small to medium-sized arteries, mainly in the brain, that leads to dementia and disability in mid-life.<br />
</quiz><br />
<br />
===Current Areas of Research and Future Directions===<br />
Notch has been identified as having a role in the development of several cancers, and therefore research has recently begun investigating the use of Notch inhibitors in cancer treatment.<ref>As reviewed by <pubmed>27732970</pubmed></ref> γ-secretase inhibitors (GSIs), which inhibit the normal cleavage of Notch at the cell membrane and hence NICD release, have been a popular area of research. In the specific case of desmoid tumours, it was observed that treatment GSIs resulted in decreases in NICD and Hes1 expression in the tumour cells. Overall, tumour cell migration and invasion were decreased and cell growth was also inhibited.<ref><pubmed>26349011</pubmed></ref> GSIs have also been shown to have an inhibitory growth effect on pancreatic, breast, and lung cancers, but unfortunately they also produce side effects ''in vivo''.<ref>As reviewed by <pubmed>27688721</pubmed></ref> Therefore continued study into GSIs is required to make them safe for human treatment. Ultimately, with ongoing research, it is possible that the Notch pathway will eventually become an effective therapeutic target for cancers.<br />
<br><br><br />
<br />
<big><b>To search and read recent PubMed research and review articles on Notch, click <u>[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=Notch here]</u>!</b></big><br />
<br><br><br />
<br />
===Want to Read More About Notch?===<br />
The [http://www.omim.org/ OMIM (Online Mendelian Inheritance in Man) database] contains extensive information about the Notch genes and associated proteins and is a great place to go if you want to find out more about the Notch pathway in humans! Click on these links to learn more about the Notch genes that encode the human receptors and ligands:<br />
<li>[http://www.omim.org/entry/190198 NOTCH1] | [http://www.omim.org/entry/600275 NOTCH2] | [http://www.omim.org/entry/600276 NOTCH3] | [http://www.omim.org/entry/164951 NOTCH4]<br />
<li>[http://www.omim.org/entry/601920 JAG1] | [http://www.omim.org/entry/602570 JAG2]<br />
<li>[http://www.omim.org/entry/606582 DLL1] | [http://www.omim.org/entry/602768 DLL3] | [http://www.omim.org/entry/605185 DLL4]<br />
<br><br><br />
<br />
You can also look at these papers for examples of reviews and research papers that reinforce the diversity of how the Notch pathway functions in organisms.<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch influences adult development as well!</big><br />
|-<br />
|Interestingly, Notch does not only play a role in human embryonic development, but has also been found to influence developmental processes after birth. One of these processes is neurogenesis, for example.<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159580/ '''Not(ch) just development: Notch signalling in the adult brain.'''] <br />
<br />
This review explains that the Notch signalling pathway, which is so often regarded as a major molecular player in development, actually has important functions related to neural cells in the adult. As you would have read in the [[#Abnormalities in Notch signalling| Abnormalities in Notch Signalling]] section, Notch abnormalities are involved in a number of diseases, which underlines its importance in maintaining adult brain function. Some highlights of this review are: Figure 2 provides a schematic representation of precise roles Notch activation can play in the adult brain; explanations of the ways that Notch influences brain plasticity; and the discussion of conflicting results of studies exploring the role of Notch in stroke recovery.<ref name=PMID21505516><pubmed>21505516</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch Modulation for Therapy</big><br />
|-<br />
|As you would have read in the [[#Abnormalities in Notch signalling| Abnormalities in Notch Signalling]] section, Notch can play different roles in cancer development. An interesting review further elucidates that modulation of Notch signalling is actually being investigated as a potential target for cancer therapy:<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704338/ '''Targeting the Notch signaling pathway in cancer therapeutics'''] <br />
<br />
This articles focuses on reviewing data emerging from recent research, explaining how Notch contributes to the development of a number of cancers, and then outlining the current focuses of investigations into how to therapeutically manipulate the Notch pathway. Some highlights from this review are: the detailed description of how Notch interacts with other signalling pathways such as Wnt and the signalling cytokine Interleukin-6; explanations of the seemingly conflicting roles of Notch as a tumour promoter and suppressor; and discussion of the findings of various Notch-related studies in cancer stem cells.<ref name=PMID26767041><pubmed>26767041</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch influences reproduction in worker honey bees!</big><br />
|-<br />
| In our [[#Roles in Animal Development| Roles in Animal Development]] section we discussed Notch in relation to a number of animals, however one that we did not cover was the worker honey bee, or ''Apis mellifera''. A recent study shows that Notch also plays a role in these honeybees!<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976197/ '''Notch signalling mediates reproductive constraint in the adult worker honeybee.'''] <br />
<br />
This research paper essentially concludes that in the worker honeybee Notch signalling constrains reproduction between males and females; they were the first team to elucidate a molecular mechanism underlying the link between adult ovary activity in bees and the presence of the queen bee. Some highlights from this unique and interesting study are: the background explanation that female worker bees have suppressed activity due to pheromones produced by the queen; the finding that Notch plays a part in this inactivation of reproductivity; and the discussion about social control of reproduction and evolution.<ref name=PMID27485026><pubmed>27485026</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch signalling is involved in embryo implantation!</big><br />
|-<br />
| Notch is essential for many developmental embryonic processes, as described in our [[#Roles in Embryonic Development|Roles in Embryonic Development]] section. Interestingly, research has shown that Notch signalling also has an important role in the initial process of establishing a successful pregnancy. Specifically, normal Notch signalling has been seen to be a critical factor in fetal-maternal communication during implantation and placentation. (To read more about these processes, go to these pages on [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Week_1_and_2_Development Weeks 1-2] and [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Week_3_Development Week 3] of development.)<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/24357662 '''Fetal-maternal communication: the role of Notch signalling in embryo implantation.''']<ref>As reviewed by <pubmed>24357662</pubmed></ref><br />
<br />
This review describes both human and animal studies of Notch signalling during pregnancy. It explains research of Notch signalling at the human blastocyst-maternal interface, and that Notch signalling has been observed in both the maternal endometrium and the blastocyst. Furthermore, Notch signalling is also important for the processes of implantation and placentation. Overall, the review summarises findings of Notch signalling in endometrial-trophectoderm interactions during the implantation, regulation of extravillous trophoblast invasion and spiral artery remodelling in the decidua, and angiogenesis in the placenta, as well as how abnormal Notch signalling is related with impaired placentation and pre-eclampsia.<br />
|}<br />
<br><br />
<br />
===Glossary===<br />
{| class="pretty table"<br />
|-<br />
| '''AER'''<br />
| 'Apical Ectodermal Ridge' is a structure that forms from the ectodermal cells at the distal end of each limb bud. The AER acts as a major signalling centre in order to ensure proper limb development.<br />
|-<br />
| '''Apoptosis'''<br />
| Programmed cell death which occurs in the development of many systems.<br />
|-<br />
| '''Calcification'''<br />
| The accumulation of calcium salts in body tissue. It normally occurs in the formation of bone, but abnormally calcium can be deposited in soft tissue causing it to harden.<br />
|-<br />
| '''Cardiogenic'''<br />
| From cardiogenesis - meaning formation of the heart.<br />
|-<br />
| '''Cardiomyocyte'''<br />
| The muscle cells (myocytes) that make up the cardiac muscle<br />
|-<br />
| '''Congenital'''<br />
| (Of a disease or physical abnormality) present from birth.<br />
|-<br />
| '''Craniofacial'''<br />
| Meaning relating to the cranium and the face.<br />
|-<br />
| '''Cyclin D1'''<br />
| A protein required for progression through the G1 phase of the cell cycle. Read more about it [https://en.wikipedia.org/wiki/Cyclin_D1 here], or see information on its encoding gene here: [http://omim.org/entry/168461 OMIM168461].<br />
|-<br />
| '''Endocardial'''<br />
| From endocardium - meaning the thin, smooth membrane which lines the inside of the chambers of the heart and forms the surface of the valves.<br />
|-<br />
| '''Endocrine'''<br />
| As in the endocrine system, refers to glands that secrete hormones or other substances directly into the blood.<br />
|-<br />
| '''Epithelium'''<br />
| The thin tissue that forms the outer layer of a body's surface and also lines the alimentary canal and other hollow structures.<br />
|-<br />
| '''Gastrulation'''<br />
| Describes the formative process of the formation of the trilaminar embryo containing the three germ layers.<br />
|-<br />
| '''Gliogenesis'''<br />
| The formation and development of glial cells (astrocytes, oligodendrocytes, Schwann cells, microglia).<br />
|-<br />
| '''Haematopoietic'''<br />
| From haematopoiesis - meaning the formation of blood cellular components<br />
|-<br />
| '''Haploinsufficiency'''<br />
| When a diploid organism has only a single functional copy of a gene (with the other copy inactivated by mutation), and so the total level of a gene product (a particular protein) produced by the cell is about half of the normal level.<br />
|-<br />
| '''Homeostasis'''<br />
| The ability to maintain a constant internal environment in response to environmental changes.<br />
|-<br />
| '''Ligand'''<br />
| A molecule that binds to a specific binding site on a protein (receptor).<br />
|-<br />
| '''Mef2C promoters'''<br />
| Myocyte-specific enhancer factor 2C is a transcription factor in the Mef2 family that is encoded by the gene ''MEF2C'' in humans ([https://omim.org/entry/600662 OMIM 600662]). This gene is involved in cardiac morphogenesis and myogenesis, as well as vascular development. It is thought to also possibly play a role in neurogenesis.<br />
|-<br />
| '''Mesenchymal'''<br />
| From mesenchyme - meaning a loosely organised, mainly mesodermal embryonic tissue which develops into connective and skeletal tissues, including blood and lymph.<br />
|-<br />
| '''Morphogenesis'''<br />
| Refers to the origin and development of morphological characteristics.<br />
|-<br />
| '''Myogenic'''<br />
| From myogenesis - meaning formation of muscle.<br />
|-<br />
| '''Myogenin'''<br />
| Also known as myogenic factor 4, this is a muscle-specific basic-helix-loop-helix transcription factor involved in the coordination of skeletal muscle development or myogenesis and repair.<br />
|-<br />
| '''Neural Crest'''<br />
| In vertebrate embryos, this is a transient structure that gives rise to most of the peripheral nervous system and to a number of non-neural cell types such as the smooth muscle cells of the cardiovascular system. <br />
|-<br />
| '''Neurogenic'''<br />
| From neurogenesis - meaning the formation of nervous tissue.<br />
|-<br />
| '''Neurulation'''<br />
| The folding process in vertebrate embryos whereby the neural plate transforms into the neural tube.<br />
|-<br />
| '''NICD'''<br />
| Notch intracellular domain<br />
|-<br />
| '''Oncogenic'''<br />
| From oncogenesis, also known as tumorigenesis or carcinogenesis - meaning the formation of a cancer, whereby normal cells are transformed into cancer cells.<br />
|-<br />
| '''Paracrine'''<br />
| A hormone that exerts an effect only in the vicinity of the gland secreting it.<br />
|-<br />
| '''Protease'''<br />
| An enzyme which breaks down proteins and peptides.<br />
|-<br />
| '''Runx2'''<br />
| Runt-related transcription factor 2 is a protein that in humans is encoded by the ''RUNX2'' gene ([http://omim.org/entry/600211 OMIM600211]). RUNX2 is an important transcription factor associated with osteoblast (bone substance-secreting cells) differentiation.<br />
|-<br />
| '''Stromal cells'''<br />
| The connective tissue cells of any organ. They support the function of the parenchymal cells of that organ. Fibroblasts and pericytes are among the most common types of stromal cells.<br />
|-<br />
|}<br />
<br />
====Further Glossary Links====<br />
[[A|A]] | [[B|B]] | [[C|C]] | [[D|D]] | [[E|E]] | [[F|F]] | [[G|G]] | [[H|H]] | [[I|I]] | [[J|J]] | [[K|K]] | [[L|L]] | [[M|M]] | [[N|N]] | [[O|O]] | [[P|P]] | [[Q|Q]] | [[R|R]] | [[S|S]] | [[T|T]] | [[U|U]] | [[V|V]] | [[W|W]] | [[X|X]] | [[Y|Y]] | [[Z|Z]] | [[Numbers|#]]<br />
<br />
===References===<br />
<references/></div>
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https://embryology.med.unsw.edu.au/embryology/index.php?title=2016_Group_Project_2&diff=255172
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{{Group Assessment Criteria table}}<br />
<!-- Do not delete the above template from the Group project page. --><br />
=The Notch Signalling Pathway=<br />
===Introduction===<br />
The Notch signalling pathway is the most prevalent form of intracellular communication in multicellular organisms. It is a critical pathway for cell differentiation, proliferation, and apoptosis. It is involved in embryonic organ development through the regulation of cell-cell signalling; specifically lateral inhibition, formation of boundaries, and cell lineage assignation.<ref name="The Developing Human">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2015). The developing human: clinically oriented embryology (10th ed.). Philadelphia: Saunders.</ref><ref name="PMID10075488">As reviewed by <pubmed>10075488</pubmed></ref> This pathway is also actively involved in adjacent cell communication, developmental process such as adult homeostasis, and stem cell maintenance. Since this pathway is an intricate and crucial aspect of an organism's development and cell signalling, a mutation in the functional components of this pathway can cause a myriad of diseases such as congenital disorders, cancers, strokes, Alagille syndrome, and leukoencephalopathy.<ref name="PMID19255248">As reviewed by <pubmed>19255248</pubmed></ref> The process of Notch signalling primarily utilises a ligand-receptor interaction to release protein fragments at the cellular membrane, which then provide signals to the internal environment of the cell and to adjacent cells. In mammals, the Notch signalling pathway is comprised of four receptors (Notch 1-4) which interact with Delta or Jagged ligands to bring about the activation of this pathway. Homologous Notch genes have been identified in other animals, such as ''Drosophila melanogaster'' (fruit fly) and ''Danio rerio'' (zebrafish).<br />
<br><br />
<br />
<big>What will you find on this wiki page?</big><br />
<br />
This page is designed to provide an overview of such features of the Notch signalling pathway, but is in no way a complete resource for all Notch-related information (especially since this signalling pathway has such a wide array of activities in many organisms and the scientific understanding of it is continuously updating!). By reading this page you should come to a better understanding of Notch in regards to: general molecular mechanisms; embryonic development by systems; examples of animal development; abnormalities and disease; current and potential future research; as well as a couple of links to interesting articles for those who want to read more. There is a [[#Glossary| Glossary]] at the bottom of the page for better understanding of scientific terms used throughout this page, and readers are encouraged to 'expand' any collapsed information on the page to optimise their experience in reading about Notch. <br />
<br><br><br />
<div align="center"><html5media width="560" height="315">https://www.youtube.com/embed/axkDX0XZyN0</html5media></div><br />
<br><br />
<br />
===History===<br />
{| class="pretty table"<br />
|-bgcolor="FAF5FF" <br />
| 1914<br />
| First description of a "notch" defect (loss of tissue in the wing) in ''Drosophila'' by John S. Dexter, giving the gene its name<ref>Dexter, J. (1914). The Analysis of a Case of Continuous Variation in Drosophila by a Study of Its Linkage Relations. ''The American Naturalist'', 48(576), 712-758. Retrieved from http://www.jstor.org/stable/2455888</ref><br />
|-<br />
| 1917<br />
| First allele of ''Notch'' is identified by Thomas Hunt Morgan<ref>Morgan, T. H. (1917). The theory of the gene. ''The American Naturalist'', 51(609), 513-544.</ref><br />
|-bgcolor="FAF5FF" <br />
|-<br />
| 1930s<br />
| Donald F. Poulson conducts research into the involvement of ''Notch'' in development.<ref><pubmed>16588136</pubmed></ref> <br />
|-<br />
| 1958<br />
| An investigation by W.J. Welshons confirmed that the locus of Notch is contained within the 3C7 band of the X chromosome.<ref><pubmed>13635554</pubmed></ref><br />
|-bgcolor="FAF5FF" <br />
|-<br />
| 1983<br />
| DNA sequences belonging to the Notch locus cloned and determined that RNA is required for the function of the wild type Notch. Further insight developed into the function of Notch and its role in differentiation and regeneration.<ref><pubmed>6403942</pubmed></ref><br />
|-<br />
| 1986<br />
| The molecular analysis and sequence of the Notch locus was determined by Michael W. Young and his team. A relationship was identified between the protein encoded by the major Notch transcript and mammalian clotting and growth factors.<ref><pubmed>3097517</pubmed></ref><br />
|-bgcolor="FAF5FF" <br />
|-<br />
| 1989<br />
| Neurogenic loci "Delta" and "Mastermind" identified and research conducted to search for genes which may have an interaction with the Notch protein. It was confirmed that mutations in these loci will affect neurogenesis.<ref><pubmed>2338245</pubmed></ref><br />
|}<br />
<br />
===Overview of Molecular Mechanisms===<br />
Mammals possess a total of four ''Notch'' genes, with five genes for encoding the associated ligands, Delta-like and Jagged. The ''Notch'' genes each code for a single transmembrane receptor. Extracellularly, it contains epidermal growth factor (EGF)-like repeats for ligand interaction and Lin-12-Notch (LN) repeats for regulating the interactions between the extracellular and intracellular regions. Intracellularly, Notch has seven ankyrin (ANK) repeats and a transactivation domain (TAD), as well as a proline, glutamine, serine, threonine-rich (PEST) domain for degradation of Notch.<br />
<br><br><br />
[[File:Notch structure cartoon.jpg|thumb|700px|center|'''The structure of the Notch receptor.'''<ref name="PMID19255248"/> Extracellularly there are epidermal growth factor (EGF)-like repeats and Lin-12-Notch repeats (LNRs). The Notch intracellular domain (NICD) is made up of a rRBP-Jkappa-associated module (RAM) domain, ankyrin (ANK) repeats, and a proline, glutamine, serine, threonine-rich (PEST) domain. There are three sites for cleavage by enzymes: S1, S2, and S3/S4.]]<br />
<br />
====Canonical pathway====<br />
[[File:Overview of Notch signalling.png|thumb|500px|'''Summary of canonical Notch signalling.''' The interaction between Delta-like or Serrate ligands (DSL) and the Notch receptor on an adjacent cell initiates proteolytic cleavage of Notch and the release of the Notch intracellular domain (NICD). The NICD is then transported to the nucleus where it can induce transcription of Notch target genes by binding to specific proteins (MAM, CSL).<ref><pubmed>27404588</pubmed></ref>]]<br />
The canonical Notch pathway is unique in that it involves direct interaction between adjacent cells, as opposed to paracrine signalling, because both the Notch ligands and Notch receptors are transmembrane proteins found in the cell membrane. Furthermore, the lack of a secondary messenger or amplification process means that the Notch pathway has limited opportunities for regulation and must therefore be tightly controlled. Depending on its developmental and cellular context, activation or inhibition of the pathway can result in a variety of cellular responses, including cell death, proliferation, or differentiation.<ref name="Introduction to Notch Signalling">Yamamoto, S., Schulze, K.L. & Bellen, H.J. (2014). Introduction to Notch Signalling. ''Notch Signaling: Methods and Protocols''. Methods in Molecular Biology: 1187</ref><br />
<br><br><br />
Four Notch proteins are involved in the canonical pathway. NOTCH1 to NOTCH4 are single transmembrane receptors and can interact with a variety of ligands, including NOTCH ligands (e.g. Delta ligands) and Serrate ligands. There are three Delta ligands (Dll1, Dll3, and Dll4) and two Serrate ligands (Jagged1 and Jagged2) present in mammals.<ref name="Introduction to Notch Signalling"/> The binding between the Notch receptor and the ligand on the adjacent cell induces the release of the Notch intracellular domain (NICD) via a sequence of proteolytic reactions.<ref name="The Developing Human"/> Cell-cell interaction is therefore critical in the process of triggering Notch signalling.<br />
<br><br><br />
The interaction on the cell surface between Notch and its ligand on an adjacent cell causes the extracellular metalloprotease site (S2 site) to be exposed. The S2 site is then cleaved by transmembrane proteases belonging to the a disintegrin and metalloproteinase/tumour necrosis factor α converting enzyme (ADAM/TACE) family. The remaining Notch fragment subsequently undergoes two more intramembranous cleavages at the S3/S4 sites by the γ-secretase complex. Finally, the NICD is released and enters the nucleus to interact with CSL (CBF1, Suppressor of Hairless, Lag-1) and Mastermind-like proteins (MAMLs). CSL is a DNA-binding protein that acts as a transcription factor by forming repressor or activator complexes; in the absence of the NCID, CSL is bound to corepressor proteins (CoR) that prevent transcription of Notch target genes. MAMLs are transcriptional co-activators that are required for transcription of the target genes, hence they are involved in the regulation of the pathway.<ref name=PMID10075488/><ref name="Introduction to Notch Signalling"/> To stop signalling, the NICD is phosphorylated by kinases and ubiquitinated by E3 ubiquitin ligases, which results in proteasome mediated degradation and subsequent termination of the signal.<ref name="Introduction to Notch Signalling"/><br />
<br><br><br />
<br />
====Non-canonical pathway====<br />
Immense research has been carried out on the canonical Notch pathway and its members are well known. While canonical notch ligands control most of the known Notch signalling, a group of structurally distinct non-canonical ligands exist which activate Notch and its pleiotropic effects. Notch can non-canonically carry out its functions by post-translationally targeting Wnt/β-catenin signalling. This type of signalling is CSL-independent and can also work independently of ligands. Some genes are affected by the non-canonical Notch signalling, however their mediators in most cases are unknown. Notch binds and titrates levels of active β-catenin. Therefore, active β-catenin activity may serve as a useful readout for non-canonical Notch signals.<ref name="PMID22397947">As reviewed by <pubmed>22397947</pubmed></ref> <br />
<br />
Recent research has shown that Notch signalling plays crucial roles for cellular differentiation during development through γ-secretase-dependent intramembrane proteolysis followed by transcription of target genes. Hayashi et al. (2016) uncovered a ligand-dependent but γ-secretase-independent, non-canonical Notch signalling involved in presynaptic protein expression in postmitotic neurons.<ref name="PMID27040987"><pubmed>27040987</pubmed></ref><br />
<br><br><br />
<br />
====Transcriptional regulation of Notch signalling====<br />
A number of genes have been found to act as modulators of Notch signalling by modifying the ability of Notch to interact with its ligands. These include proteins acting extracellularly (Fringe, Brainiac, Egghead, Scabrous, Wingless), proteins acting at the cell membrane (Big brain), proteins acting intracellularly (Numb, Sanpodo, Disabled, Deltex, Dishevelled), and proteins acting within the nucleus (Hairless, EMB-5, Strawberry notch).<ref name="PMID9892565">As reviewed by <pubmed>9892565</pubmed></ref><br />
<br />
In ''Drosophila melanogaster'', it has been seen that ''fringe'' is able to affect the ability of Notch to be activated by the Serrate and Delta ligands. Specifically in the ''Drosophila'' wing, it was observed that Serrate did not interact with Notch in specific areas due to the action of ''fringe''<ref><pubmed>9247339</pubmed></ref>. Fringe is not required for initial Notch signalling, but is thought to be important for signalling processes when Notch activation occurs along the borders between distinct cell populations. Research suggests that Fringe specifically affects the binding between Notch and its ligands, rather than an activation step separate or subsequent to ligand binding. The ''brainiac'' and ''egghead'' genes are thought to either influence the production of a Notch ligand or act as substitute ligands themselves.<ref name="PMID9892565"/><br />
<br><br><br />
<br />
====Examples of Proteins Involved in Interaction with the Notch Intracellular Domain <small>(adapted from Table 3<ref name="PMID21828089"/>)</small>====<br />
{| class="pretty table"<br />
|-bgcolor="A3BFB1" <br />
| '''Protein'''<br />
| '''Interaction with NICD'''<br />
|-bgcolor="F5FFFA"<br />
| Adenamatous polyposis coli (Apc)<br />
| Controls Notch trafficking<br />
|-<br />
| Cyclin-dependant kinase 8 (CDK8)<br />
| Phosphorylates NICD to make it a substrate for ubiquitylation and degradation<br />
|-bgcolor="F5FFFA"<br />
| CBF1, Su(H) and LAG-1/Recombination signal binding protein for immunoglobulin kappa J region (CSL/RBP-J)<br />
| Main canonical transcriptional co-factor for NICD<br />
|-<br />
| Cyclin C (CycC)<br />
| Targets NICD for phosphorylation to make it a substrate for ubiquitylation and degradation<br />
|-bgcolor="F5FFFA"<br />
| Dishevelled (Dsh/Dvl)<br />
| Controls ligand-independent Notch trafficking; inhibits canonical Notch signalling<br />
|-<br />
| Deltex-1-4 (Dtx1-4)<br />
| Controls Notch ubiquitylation, processing, and internalisation<br />
|-bgcolor="F5FFFA"<br />
| Itchy, E3 ubiquitin protein ligase (Itch)<br />
| Promotes ubiquitylation of NICD<br />
|-<br />
| Mastermind-like 1/2 (Maml1/2)<br />
| Co-activator for NICD/CSL<br />
|-bgcolor="F5FFFA"<br />
| Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-ϰb)<br />
| NICD blocks NF-ϰb transcription of NF-ϰb target genes through binding to p50/cRel<br>NICD enhances NF-ϰb transcription of target genes by retaining NF-ϰb in the nucleus<br />
|-<br />
| Numb homolog (Numb)<br />
| Suppresses Notch signaling by recruiting E3 ubiquitin ligases to ubiquitylate Notch<br>Controls Notch trafficking during asymmetric cell division<br />
|-bgcolor="F5FFFA"<br />
| Smad family members (SMAD)<br />
| Smads enhance Notch signalling; Notch fine-tunes signalling through Smads<br />
|}<br />
<br><br />
<br />
===Roles in Embryonic Development===<br />
The phylogenetically conserved Notch signalling pathway plays a crucial role in the development of multiple organ systems, and is a major regulator of stem cell fate. It is responsible for the regulation of the transcription of a number of signalling molecules, such as ''MyoD'', ''Mash1'' and ''GATA2'', which are genes controlling the fate of myogenic, neurogenic and haematopoietic stem cells, respectively. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> The following subsections will further elucidate the vital roles of Notch signalling during normal embryonic development. If you would like to better understand human embryonic development before reading this section, [https://embryology.med.unsw.edu.au/embryology/index.php/Embryonic_Development| this page] serves as a great resource. <br />
<br><br><br />
<br />
====Cardiovascular====<br />
<br />
If you would like to generally learn about and become familiar with cardiac development in the embryo before reading this section, click [https://embryology.med.unsw.edu.au/embryology/index.php/ANAT2341_Lab_11_-_Heart here]!<br />
<br />
'''Cardiomyocyte Specification and Differentiation'''<br />
<br />
Expression during the appropriate window of the timeline of embryogenesis of Notch receptors, ligands and downstream effector molecules elucidates a role for the Notch pathway in the earliest stages of cardiac development. It has been found to restrict the expression of specific cardiogenic genes in a spatiotemporal manner and regulate cardiac field specification as early as during gastrulation. <ref name=PMID19580804><pubmed>19580804</pubmed></ref> Interestingly, Notch has been found to play both suppressive and promoting roles in cardiogenesis.<br />
<br />
For example, it has been shown that Notch suppresses cardiomyocyte cell fate specification during early cardiogenesis. This has been demonstrated through studies such as that carried out by Rones and colleagues (2000), which used activation and inhibition of Notch signaling in Xenopus. <ref name=PMID10934030><pubmed>10934030</pubmed></ref><br />
<br />
On the other hand, studies such as that by Boni et al. (2008) have found that Notch signalling may also promote myogenesis from cardiac progenitor cells. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> Cardiogenesis has also been promoted by downregulating Notch-1 activity in stem cells of embryos (Nemir et al., 2006).<ref name=PMID16690879><pubmed>16690879</pubmed></ref><br />
<br />
Despite the understanding that Notch signalling is crucial to embryonic myogenesis, the exact molecular mechanism remains elusive. Research by Buas and colleagues (2010) has explored such mechanisms by studying the Notch target, Hey1, which is known to suppress myogenic differentiation. They concluded that this inhibitory function of Hey1 is primarily mediated through binding near to myogenin and Mef2C promoters, which leads to cessation of target gene expression. <ref name=PMID19917614><pubmed>19917614</pubmed></ref><br />
<br />
[[File:Notch CVS simple diagram.png|thumb|500px|right|alt=Simplified Scheme of the Roles of Notch in Cardiac Development|'''Simplified Scheme of the Roles of Notch in Cardiac Development.''' Notch has been found to restrict the expression of specific cardiogenic genes in a spatiotemporal manner and regulate cardiac field specification early in development. Further after cardiac differentiation, Notch influences development of the AVC (atrioventricular canal), cardiac valves, ventricular trabeculae and the cardiac outflow tract. (This student-drawn image is based upon Figure 2 in the 2014 review by Zhou and Liu: [https://www.ncbi.nlm.nih.gov/pubmed/24345875 ''Role of Notch signaling in the mammalian heart.'']<ref name=PMID24345875><pubmed>24345875</pubmed></ref>)]]<br />
<br />
'''Development of the Atrioventricular Canal'''<br />
<br />
A study by Rutenberg et al. (2006) and another by Kokubo et al. (2007) implicate a role for Notch signaling in the region between the atria and the ventricles of the heart (the atrioventricular canal, or AVC).<ref name=PMID17021042><pubmed>17021042</pubmed></ref> <ref name=PMID17259303><pubmed>17259303</pubmed></ref> They used chicken and mouse models, respectively, to show that other signalling factors, ''Bmp2'' and ''Tbx2'', are restricted to the AVC region by Notch signalling during development. <br />
<br />
Furthermore, Watanabe and colleagues (2006) showed that deletion of Notch targets increases ''Bmp2'' expression and expansion of the AVC tissue, however other, non-Notch restrictive factors involved in AVC development are likely to exist.<ref name=PMID16554359><pubmed>16554359</pubmed></ref> <br />
<br />
'''Heart Valve Development'''<br />
<br />
In order for the heart valve to properly form in the embryo, endocardial to mesenchymal transformation (EMT) must occur. The Notch pathway, alongside Wnt and Bmp, has been found to regulate the process of EMT, defects in which can lead to congenital heart valve disease. Interestingly, Timmerman and colleagues (2004) demonstrated that this role of Notch may also promote oncogenic transformation. This team also showed that embryos exhibited abortive endocardial EMT if they were deficient in Notch signalling components in vivo and in vitro. <ref name=PMID14701881><pubmed>14701881</pubmed></ref> <br />
<br />
A more recent paper by Wang et al. (2013) further explored the underlying signalling processes and interrelationships of molecules that impact EMT. They found that Jagged1-Notch1 signalling in cells of the endocardium potentiates expression of Wnt4, which in turn carries out paracrine action on adjacent AVC tissue to upregulate Bmp2 expression and thus signal EMT. <ref name=PMID23560082><pubmed>23560082</pubmed></ref><br />
<br />
'''Trabeculation'''<br />
<br />
Trabeculation is the initial process of ventricular chamber development that forms a series of cardiomyocyte projections within the lumens of the ventricles of the heart (called trabeculae). Grego-Bessa and colleagues (2007) addressed the roles Notch plays in trabeculation through ''RBPJk'' (the gene product of which interacts with Notch) and ''Notch1'' gene manipulation. Mutants of these two genes showed perturbed expression and signalling of ''EphrinB2'', ''NRG1'' and ''BMP10'', alongside reduced proliferation of myocardiocytes. This research ultimately suggested that ''EphrinB2'' is a direct target of Notch in the endocardium that simultaneously requires the Notch-dependent action of BMP10 and NRG1 in order for ventricular myocardium proliferation and differentiation to occur normally. <ref name=PMID17336907><pubmed>17336907</pubmed></ref> Furthermore, the important process of trabeculation has recently been shown to be controlled by sequential Notch activation by an investigation by D’Amato et al. (2015). <ref name=PMID26641715><pubmed>26641715</pubmed></ref><br />
<br />
'''Development of the Outflow Tract'''<br />
<br />
About one third of congenital heart defects include malformations in the outflow tract which include the aorta, pulmonary arteries, aortic arch and ductus arteriosus. During cardiogenesis, neural crest cells interact with second heart field myocardium and endocardial mesenchyme. <ref><pubmed>20201902</pubmed></ref> <br />
Studies involving neurogenesis demonstrated the sensitivity of Notch signaling to temporal and spatial cues and showed the early Notch signaling initially controls the number of cells with a neurogenic fate and later dictates the lineage decision of neural versus glial cell fate. <ref><pubmed>16429119</pubmed></ref><br />
Neural crest precursors for ideal patterning of the outflow tract are required in the Notch signaling pathway. The use of a dominant negative form of a master mind like protein (MAML) which has shown to be a pan Notch inhibitor in neural crest cells inactivates Notch signaling. This results in congenital heart defects like pulmonary artery stenosis and aortic arch patterning defects associated with defects in smooth muscle formation. <ref><pubmed> 17273555 </pubmed></ref><br />
Part of the phenotype in defective neural crest cells is attributed to loss of Notch2 signalling as Notch2 inactivation in these cells produces small caliber aortas and pulmonary arteries because of defects in smooth muscle. <ref><pubmed> 18330927 </pubmed></ref><br />
Jagged1 is the ligand involved which signals to Notch on neural crest cell surfaces to induce vascular smooth muscle cell differentiation. <ref><pubmed> 18245384 </pubmed></ref><br />
Mutations in both JAGGED1 and NOTCH2 genes have been known to cause Alagille syndrome, further substantiating the importance of this pathway in proper formation of the outflow tract. <ref><pubmed> 16575836 </pubmed></ref><br />
<br />
Another study by Garg stresses the importance of Notch signaling in the outflow tract region. NOTCH1 mutations were seen in patients with aortic stenosis. Aortic stenosis results from the calcification of the aortic valve and is quite common in adults. However, in children, this may result in failure of the left ventricle to develop properly. NOTCH1 haploinsufficiency is also linked to early calcification and bicuspid aortic valve disease. This could be due to an early induction of Runx2 through the HRT genes.<br />
<ref><pubmed> 16025100 </pubmed></ref><br />
<br />
<br><br><br />
<br />
====Central Nervous System====<br />
<br />
If you would like to generally learn about and become familiar with neural development in the embryo before reading this section, click [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Neural_Development here]!<br />
<br />
[[File:Notch CNS simple diagram.png|thumb|450px|right|alt=Simplified Diagram of Roles of Notch in Neuronal Differentiation|'''Simplified Diagram of Roles of Notch in Neuronal Differentiation'''. Notch influences the differentiation of embryonic stem cells into neural cells via signalling with RBP (recombining binding protein), cyclin D1 and Hes1. (This student-drawn image is based upon Figure 1 from Chuang, Tung and Lin's 2015 review: [https://www.ncbi.nlm.nih.gov/pubmed/25815127 ''Neural differentiation from embryonic stem cells in vitro: An overview of the signaling pathways'']<ref name="PMID25815127"><pubmed>25815127</pubmed></ref>)]]<br />
'''Early Neural Differentiation'''<br />
<br />
Notch plays a major role in promoting neural commitment of cells. Lowell and colleagues (2011) used genetic manipulation to discover that the phenotype of stem cells is not affected by constitutively activated Notch in mouse embryonic stem cells (mESCs), however, interfering with Notch signalling -for example by pharmacological means- did impede neural fate determination. This role required Notch signalling via fibroblast growth factor (FGF) receptors. Furthermore, the conservation of the Notch signalling pathway within pluripotent stem cells is implied due to the existence of Notch ligands in stromal cells in human embryonic stem cells (hESCs) that induce neural differentiation. <ref name=PMID16594731><pubmed>16594731</pubmed></ref><br />
<br />
Das and colleagues (2010) manipulated Notch protein levels during specific stages of neural differentiation and found that if Notch signalling pathways were activated during day 3 of neural development for 6 hours, cell proliferation was dramatically enhanced. This was attributed to the induction by Notch of cyclin D1 expression. Without Notch signalling during neural development, there was reduced cyclin D1 levels. Manipulation of mESCs to express a dominant negative form of cyclin D1 resulted in abrogation of cell proliferation stimulated by Notch. Overall these results imply a temporally-specific role for Notch in CNS development, and that it requires cyclin D1 as a signalling molecule.<ref name=PMID20887720><pubmed>20887720</pubmed></ref><br />
<br />
Hes1 has also been shown to play a Notch-mediated role in neural progenitor maintenance, which is essential for proper development since cells need to proliferate only during specific periods in the embryo for the correct number, cell type and function to result. Shimojo, Ohtsuka and Kageyama (2008) used real time imaging in mice to show that Notch induces oscillatory expression of ''Hes1'' and other Notch target genes to maintain the complex temporal organisation of events in neural development. They concluded that further research could elucidate more about Hes1 oscillations in regards to neural progenitor maintenance, proliferation and differentiation <ref name=PMID18400163><pubmed>18400163</pubmed></ref>.<br />
<br />
Lastly, as well as influencing neural progenitor differentiation, it has been found that Notch also impacts the development and maintenance of polarised neural structures in the embryo. This was concluded from a knockout study in mice that elucidated a role for RBP (recombining binding protein), downstream of Notch, in modulating neural differentiation and maintaining rosette structure (an experimental ''in vitro'' correlate used for neural tube development) <ref name=PMID23675446><pubmed>23675446</pubmed></ref>. The researchers concluded that RBP knockouts lacked canonical Notch signalling and as a result showed multiple neurulation defects.<br />
<br><br><br />
<br />
====Other Systems====<br />
<br />
As aforementioned, Notch plays a wide array of roles in embryonic development, the follow table summarises these roles by each organ system:<br />
<br />
<big>Summary Table of Examples of Notch Signalling in Developmental Processes</big> <small>(adapted from Table 1<ref name="PMID21828089">As reviewed by <pubmed>21828089</pubmed></ref>)</small><br />
{| class="pretty table"<br />
|-bgcolor="CEDFF2"<br />
| '''Organ/Tissue'''<br />
| '''Processes regulated by Notch'''<br />
|-bgcolor="F5FAFF" <br />
| Brain<br />
| Controls the balance between gliogenesis and neurogenesis; stem cell maintenance<ref><pubmed>21262462</pubmed></ref><ref>As reviewed by <pubmed>20816397</pubmed></ref>; organisation and maintenance of polarity during early development<ref name="PMID23675446"/><br />
|-<br />
| Craniofacial structures<br />
| Palate morphogenesis: loss of Notch signalling results in cleft palate, fusion of the tongue with the palatal shelves, and other craniofacial defects; also involved in tooth development<br />
|-bgcolor="F5FAFF"<br />
| Ear<br />
| Defines the presumptive sensory epithelium; determines hair cell and supporting cell fates<br />
|-<br />
| Esophagus<br />
| Regulates esophageal epithelial homeostasis<br />
|-bgcolor="F5FAFF"<br />
| Heart<br />
| Cardiac patterning, cardiomyocyte differentiation, valve development, ventricular trabeculation, outflow tract development<br />
|-<br />
| Intestine<br />
| Controls proliferation and differentiation, including absorptive vs. secretory cell fates<br />
|-bgcolor="F5FAFF"<br />
| Limbs<br />
| Apical ectodermal ridge (AER) formation and digit morphogenesis, especially regulation of apoptosis<br />
|-<br />
| Lungs<br />
| Lateral inhibition between tracheal cells prevents extra cells from assuming the lead position during tracheal branching morphogenesis<br />
|-bgcolor="F5FAFF"<br />
| Neural crest<br />
| Controls patterning of neural crest precursors for the outflow tract region of the heart; regulates the transition from Schwann cell precursor to Schwann cell, controls Schwann cell proliferation and inhibits myelination; controls melanocyte stem cell maintenance<br />
|-<br />
| Pancreas<br />
| Specifies endocrine cell differentiation through lateral inhibition: endocrine lineage cells inhibit endocrine differentiation of their neighboring cells; maintains pancreatic endocrine precursor cells, inhibits terminal acinar cell differentiation; controls pancreatic epithelium branching and bud size<br />
|-bgcolor="F5FAFF"<br />
| Skin<br />
| Regulates cell adhesion, control of proliferation, hair follicle or feather papillae differentiation and homeostasis<br />
|-<br />
| Thyroid<br />
| Regulates the numbers of thyrocyte and C-cell progenitors and regulates differentiation and endocrine function of thyrocytes and C-cells<ref><pubmed>21364918</pubmed></ref><br />
|-bgcolor="F5FAFF"<br />
| Vasculature<br />
| Regulates arteriovenous specification and differentiation in endothelial cells and vascular smooth muscle cells; regulates blood vessel sprouting and branching<br />
|}<br />
<br />
====Quiz Your Notch-Knowledge on Embryonic Development!====<br />
<br />
<quiz display=simple><br />
<br />
{ In the development of which organ does Notch exert lateral inhibition to differentiate endocrine cells?<br />
|type="()"}<br />
- &nbsp; The heart<br />
- &nbsp; The central nervous system<br />
- &nbsp; The skin<br />
+ &nbsp; The pancreas<br />
|| Remember, Notch signals endocrine lineage cells of the developing pancreas to inhibit endocrine differentiation of their neighbouring cells, known as lateral inhibition. Notch plays various roles in the heart, central nervous system and skin, but not in this way. <br />
</quiz><br />
<br><br />
<br />
===Roles in Animal Development===<br />
The Notch signalling pathway doesn't just play a significant role in human development, but also affects events such as neurogenesis and myogenesis in some animals (thus why these animals are often used as models for human development in research!). Read below for information on some of these roles for Notch.<br />
<br><br><br />
<br />
[[File:Notch animals.png|thumb|450px|right|alt=Animals Whose Developmental Processes are Affected by Notch.|'''Animals Whose Developmental Processes are Affected by Notch.''' This is a simplified representation of a few examples of the animals (Drosophila flies<ref name=PMID21447553><pubmed>21447553</pubmed></ref>, C. elegans<ref name=PMID18599512><pubmed>18599512</pubmed></ref>, and the zebrafish<ref><pubmed>23840804</pubmed></ref>) in which development is influenced by the Notch signalling pathway, and their scientific names.]]<br />
<br />
====''Drosophila melanogaster''====<br />
<br />
'''(The Fly)'''<br />
<br />
Unlike the four Notch paralogs in humans, only one Notch homolog is present in ''Drosophila''.<ref name="Introduction to Notch Signalling"/><br />
<br />
Both canonical and non-canonical Notch signalling are involved in the structural and physiological responses and functional plasticity of olfactory receptor neurons in reaction to prolonged odour exposure.<ref><pubmed>26986723</pubmed></ref><ref><pubmed>26011623</pubmed></ref> Research has also shown that Notch is crucial for the formation of longitudinal connections in the Drosophila CNS. Kuzina, Song, and Giniger (2011) created temperature-sensitive mutations of Notch genes that prevented the development of mature longitudinal axon tracts. Additionally, it was found that the Notch phenotype appears at the earliest stages of the development of longitudinal connections in the CNS by observing early stage 13 embryos.<ref name=PMID21447553><pubmed>21447553</pubmed></ref><br />
<br><br><br />
<br />
====''Caenorhabditis elegans''====<br />
<br />
'''(The Worm)'''<br />
<br />
The Notch pathway in ''C. elegans'' occurs throughout development in populations of equipotent cells for neuronal function in postmitotic differentiated neurons. In these postmitotic neurons, there is a specialised post-embryonic development stage knows as 'dauer'. The Notch pathway is activated when cell signalling downstream of the developmental decision enter dauer. The Notch receptor glp-1 and the ligand lag-2 are expressed in the dauer stage and aid in maintaining this stage. Another Notch receptor, lin-12, functions upstream of insulin signalling components to promote conditions for growth and enhance dauer recovery. <ref name=PMID18599512><pubmed>18599512</pubmed></ref><br />
<br><br><br />
<br />
====''Danio rerio''====<br />
<br />
'''(The Zebrafish)'''<br />
<br />
The expression of Notch in the myogenic region and apical ectodermal ridge (AER) of the developing zebrafish fin is similar to what has been observed in developing chicken and mouse limbs, which shows how highly conserved the role of Notch signalling is in the development of appendages in vertebrates. During zebrafish embryogenesis, the timing and positioning of fin formation are dependent on Notch signalling. Notch is also involved in the actual processes of fin formation, such as AER signalling, chondrogenic differentiation, and myogenesis. In zebrafish embryos with defective Notch signalling, it was observed that the skeletal muscle fibres were thin and fragmented and the structure of the sarcomeres was significantly compromised. <ref name="PMID23840804"><pubmed>23840804</pubmed></ref><br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Expand this for an image from this research study</big><br />
|-<br />
|[[File:Abnormal pectoral fins are formed in Notch signalling disrupted larvae.jpg|thumb|450px|right|alt=Abnormal pectoral fins are formed in Notch signalling disrupted larvae|'''Abnormal pectoral fins are formed in Notch signalling disrupted larvae.''' (A–F) Live pictures of 5 dpf larvae. (A’) A pectoral fin from a sibling embryo showing the cartilaginous endoskeletal disc with individualized cells surrounded by thin matrix deposits, the fin fold and the chleitrum (n = 17) (E, E’). A similar pectoral fin was found in a DMSO-treated embryo (n = 9). Pectoral fins of Notch signalling disrupted embryos such as mibta52b (n = 18) (B, B’), jagged2 (n = 10) (C, C’) and Su(H)1+2 (n = 12) (D, D’) morphants and DAPT-treated embryos (n = 10) (F, F’) showing disorganized endoskeletal disc cells. cl, chleitrum; ed, endoskeletal disc; ff, fin fold.<ref name="PMID23840804"/>]]<br />
|}<br />
<br><br><br />
<br />
====Quiz Your Notch-Knowledge on Animal Development!====<br />
<br />
<quiz display=simple><br />
<br />
{In which animal (as described in this section) has it been shown that defective notch signalling leads to thinning and fragmentation of skeletal muscle fibres?<br />
|type="()"}<br />
- &nbsp; Drosophila melanogaster<br />
- &nbsp; I don't know!<br />
- &nbsp; Caenorhabditis elegans<br />
+ &nbsp; Danio rerio<br />
|| Remember, it was observed in one study that the skeletal muscle fibres of zebrafish (Danio rerio) were thin and fragmented and the structure of their sarcomeres were significantly compromised.<ref><pubmed>23840804</pubmed></ref> <br />
</quiz><br />
<br />
===Summary of Functions of Proteins Involved in Notch Signalling <small>(adapted from Table 1<ref name="PMID17761886"><pubmed>17761886</pubmed></ref>)</small>===<br />
{| class="pretty table"<br />
|-bgcolor="a3bfb1"<br />
| '''Mammals'''<br />
| '''''Drosophila'''''<br />
| '''''C.elegans'''''<br />
| '''Function'''<br />
|-bgcolor="F5FFFA" <br />
| Notch 1-4<br />
| Notch<br />
| Lin-12, Glp-1<br />
| Single transmembrane receptor and transcription factor<br />
|-<br />
| Delta 1, Delta3-4, Jagged1-2<br />
| Delta, Serrate<br />
| APX-1, LAG-2, ARG-1, DSL-1<br />
| Single transmembrane ligands of the Notch receptor<br />
|-bgcolor="F5FFFA" <br />
| CBF1/RBPJK<br>Mastermind1-3<br />
| Su(H)<br>Mastermind<br />
| Lag-1<br>Lag-3<br />
| DNA-binding transcription factor<br>Transcriptional co-activator<br />
|-<br />
| Lunatic, manic, and radical Fringe<br />
| Fringe<br />
|<br />
| Modifies both Notch and its ligands<br />
|-bgcolor="F5FFFA" <br />
| ADAM10, ADAM17<br />
| Kuzbanian, Kuzbanian-like, TACE<br />
| SUP-17, ADM-4<br />
| Metalloproteases targeting S2 Notch cleavage sites<br />
|-<br />
| Presenilin 1-2, nicastrin, APH1, PEN2<br />
| Presenilin, nicastrin, APH1, PEN2<br />
| SEL-12, APH-1, APH-2, PEN2<br />
| Proteins of the γ-secretase complex, which targets Notch S3 and S4 cleavage sites<br />
|-bgcolor="F5FFFA" <br />
| Mind bomb, skeletrophin, neuralized 1-2<br />
| Mind bomb 1-2, neuralized<br />
| Y47D3A.22<br />
| E3 ubiquitin-protein ligases that targets Delta and Jagged/Serrate and regulate their endocytosis<br />
|}<br />
<br><br />
<br />
===Abnormalities in Notch Signalling===<br />
Mutations in Notch genes and hence defects in Notch signalling have been implicated in the pathogenesis of several inherited diseases in humans.<ref name="PMID23729744">As reviewed by <pubmed>23729744</pubmed></ref><ref name="PMID22306179">As reviewed by <pubmed>22306179</pubmed></ref> The diseases listed in this summary table are only a few examples and are described in more detail below.<br />
<br><br />
<br />
{| class="pretty table"<br />
|-bgcolor="CEDFF2" <br />
| '''Disease'''<br />
| '''Gene'''<br />
| '''Phenotype'''<br />
|-bgcolor="F5FAFF" <br />
| Alagille syndrome ([http://omim.org/entry/118450 OMIM118450], [http://omim.org/entry/610205 OMIM610205])<br />
| ''JAG1'', ''NOTCH2''<br />
| Developmental abnormalities of the heart, liver, eye, and skeleton. Neonatal jaundice and cholestasis are early symptoms.<br />
|-<br />
| CADASIL ([http://omim.org/entry/125310 OMIM125310])<br />
| ''NOTCH3''<br />
| Autosomal vascular disorders linked to ischemic strokes, dementia, and premature death.<br />
|-bgcolor="F5FAFF"<br />
| T-cell acute lymphoblastic leukaemia ([http://omim.org/entry/613065 OMIM613065])<br />
| ''NOTCH1'' (mutation in heterodimerization domain or PEST domain)<br />
| Tumour derived from T-cell progenitors. Symptoms include anaemia and enlargement of lymph nodes in the liver and/or spleen.<br />
|-<br />
| Spondylocostal dysostosis ([http://omim.org/entry/122600 OMIM122600])<br />
| ''DLL3'', Lunatic fringe<br />
| Vertebral segmentation defects as well as rib abnormalities.<br />
|}<br />
<br />
====Alagille Syndrome====<br />
Alagille syndrome (AGS) is an autosomal dominant, multisystem disorder that mainly affects the liver, heart, and kidney. Diagnostic characteristics of the disease include liver disease, cardiac disease, vertebral defects, eye conditions, and facial features, as well as renal and vascular abnormalities.<ref>As reviewed by <pubmed>26548814</pubmed></ref> Two variants of AGS, type 1 and type 2, have been identified, and each is related to different defects in the Notch pathway. In clinically diagnosed cases of AGS type 1 (which accounts for approximately 97% of all cases of AGS), a mutation in the gene encoding the Notch ligand Jagged1 (Jag1) has been identified as a contributing factor.<ref>As reviewed by <pubmed>11745040</pubmed></ref> In the much rarer AGS type 2, a mutation in the NOTCH2 gene has been implicated in the manifestation of AGS. The mechanisms by which mutations in JAG1 and NOTCH2 lead to pathogenesis of AGS are not well understood, but it is known that normal Notch signalling is important in angiogenesis. Therefore, it is thought that abnormal JAG1 or NOTCH2 will cause disruptions to the pathway that leads to the vascular disorders present in AGS. This is also evidenced by research that JAG1 knockout mice suffer premature death due to vascular defects.<ref>As reviewed by <pubmed>21934706</pubmed></ref> It is possible that AGS caused by a mutation in NOTCH2 alone will lead to a different presentation than AGS patients with mutated JAG1; however, this is still undergoing further research. It is also unclear why AGS type 2 occurs at a significantly lower incidence than AGS type 1.<ref><pubmed>16773578</pubmed></ref><br />
<br><br><br />
<br />
====Spondylocostal Dysostosis====<br />
Spondylocostal Dysostosis (SD) is a collective term for conditions characterised by anomalies relating to rib and spine. The vertebrae are fused and shaped abnormally which can result in scoliosis. Similarly, the ribs may also be fused together or in some cases completely missing. As a result, people with this condition have short trunk dwarfism where their bodies are short in stature but have normal length limbs. Genetic changes are known to cause SD. SD Type 1 is the most prevalent form of this disease which is caused by the mutation in the delta like canonical Notch ligand 3 (DLL3 gene).<ref><pubmed>10742114</pubmed></ref> DLL3 provides the information for making a protein that regulates the Notch signalling pathway. The DLL3 protein in conjunction with the Notch pathway is primarily responsible for preventing the fusion of future vertebrae in a process known as somite segmentation.<ref><pubmed>11236715</pubmed></ref> An interruption in the Notch pathway inhibits the somite segmentation resulting in abnormalities relating to the ribs and spine as seen in SD. 25 percent of SD arise from mutations in the identified genes and further research suggest that other genes involved in the Notch signalling pathway may also be related to SD.<br />
<br><br><br />
<br />
====Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)====<br />
CADASIL is an autosomal-dominant disease of the small to medium-sized arteries, mainly in the brain, that leads to dementia and disability in mid-life. The symptoms, age of onset, and prognosis are variable. Distinguishing symptoms include subcortical ischemic events (60-80% of cases), cognitive impairment (60% of late stage disease), migraines (30-40%), mood disturbances (30%), and apathy (40%).<ref name="PMID21045164"><pubmed>21045164</pubmed></ref><ref name="PMID20301673"><pubmed>20301673</pubmed></ref> Approximately 5-10% of CADASIL patients also experience seizures. The mean age of onset is 45 years of age and the disease duration is between 10–40 years. More than 95% of CADASIL cases present with pathogenic mutations in NOTCH3 (located on chromosome 19p13), specifically the epidermal growth factor-like repeat domain.<ref name="PMID20301673"/><ref><pubmed>24579972</pubmed></ref> The NOTCH3 gene is involved in the normal development of blood vessels in both fetal and adult brains. In adults, NOTCH3 is expressed in the smooth muscle cells of arteries.<ref name="PMID21045164"/> There is currently no effective treatment available for CADASIL.<br />
<br><br><br />
<br />
====Congenital Heart Defects====<br />
<br />
'''Aortic Valve Disease'''<br />
<br />
[[File:Aortic valve disease.jpg|thumb|450px|right|alt=Loss of NOTCH1 expression in proximity to calcific nodules in human aortic valves|'''Loss of NOTCH1 expression in proximity to calcific nodules in human aortic valves.''' (A) Representative sections from control (A,B) and diseased (C-F) aortic valve cusps. (B) is high magnification image of boxed area in (A) and (D,E) are higher magnification of region in (C) while image in (F) shows another calcified aortic valve. Expression of Notch1 intracellular domain (NICD) is found in the thickened fibrosa of diseased aortic valve (C,E) as compared to the acellular fibrosa of control valves (A,B). However, there is significant loss of NICD expression in cells residing adjacent to calcific nodules (D,F). The fibrosa is oriented upward in all panels, and scale bars equal 100 microns (B,D,E,F are at same magnification). Brown signal represents NICD expression while nuclei are counterstained in blue.<ref name="PMID22110751"><pubmed>22110751</pubmed></ref>]]<br />
<br />
Calcification of the aortic valve is a leading cause of adult heart disease. Mutations in NOTCH1 have been found to cause various aortic valve abnormalities, including the development of a bicuspid aortic valve (as opposed to tricuspid) and valve calcification.<br />
<br />
&emsp;&emsp;A study by Garg et al. (2005) looked at mouse embryos and the expression of ''Notch1'' during development. It was found that during normal embryonic development, ''Notch1'' was abundantly expressed in the outflow tract mesenchyme (which develops into the heart valves) and the endocardium, as well as in the endothelial layer and mesenchyme of the aortic valve leaflets at the time of arterial trunk septation. Abnormal ''Notch1'' led to the death of mice from vascular endothelial defects. Garg et al. then investigated whether NOTCH1 was involved in calcium deposition and therefore valve calcification. This is thought to be due to differentiation of valve cells into osteoblast-like cells. This leads to the upregulation of osteopontin, osteocalcin, and other osteoblast-specific genes, which is normally regulated by the transcription factor Runx2. Runx2 is known to be upregulated in animal models of valve calcification. Garg et al. found that Notch1 was capable of repressing Runx2 activation. Heart tissue and vasculature are normally abundant with the hairy-related transcriptional repressors Hrt1 and Hrt2 (also called Hey1 and Hey2), which are normally activated by Notch and are key mediators of the Notch pathway. Hrt1 and Hrt2 were both expressed in the endothelium of the mice aortic valve leaflets, the endocardium, and the vascular endothelium. They were found to inhibit the activation of osteoblast-specific genes by Runx2. It was thought that Hrt proteins can repress Runx2 by physical interaction as well as mediate Notch1 repression of Runx2. Therefore, a defect in Notch will cause upregulation of Runx2, due to the lack of repressor activity by Notch itself and the activation of the repressors Hrt1 and Hrt2. This leads to the expression of osteoblast genes that results in the differentiation of valvular cells into osteoblast-like cells and ultimately causes aortic valve calficiation.<ref><pubmed>16025100</pubmed></ref><br />
<br />
The picture to the right is a histological image of aortic valve disease from a study performed in rats investigating molecular changes that occurred when Notch signalling was suppressed in the aortic valve.<ref name="PMID22110751"/><br />
<br><br><br />
<br />
====Tumourigenesis====<br />
Notch has been shown to be involved in cancer development and can act as both an oncogene and a tumour suppressor gene.<ref>As reviewed by <pubmed>14570040</pubmed></ref><ref name="PMID23729744"/> Defective Notch signalling has been implicated in the pathogenesis of several human cancers, such as acute myelogenous leukemia (overexpression of Jagged1 and Notch1), multiple myeloma (overexpression of Jagged1/2 and Notch1/2), and B-cell–derived Hodgkin lymphoma (overexpression of Jagged1 and Notch1).<ref name="PMID16291593">As reviewed by <pubmed>16291593</pubmed></ref><br />
<br />
Elevated levels of Notch ligand proteins and/or mRNA have been observed in several cancers. Upregulated Jagged1 mRNA has been seen in human pancreatic cancer; Jagged1 protein overexpression has also been studied in prostate, cervix, and brain cancers. Cervical cancers have shown upregulated Jagged2 mRNA. Additionally, elevated Dll1 mRNA has been observed in cervical cancers, as well as in human brain cancers at both Dll1 mRNA and protein levels. Additionally, defective Notch receptor expression has been implicated in cancer as well. For example, elevated Notch1 protein expression has been found in cervical, colon, lung, pancreas, skin, and brain cancers. Protein overexpression of Notch3 and Notch4 has also been seen in malignant melanoma and pancreatic cancer.<ref name="PMID16291593"/><br />
<br />
Interestingly, research has shown that Notch signalling can also have a tumour-suppressive effect. Studies have indicated that Notch signalling can inhibit proliferation and even stimulate apoptosis in malignant B-cells. Furthermore, the Notch1 intracellular domain has also shown the ability to induce growth arrest and apoptosis in Hodgkin lymphoma and multiple myeloma cells.<ref name="PMID16291593"/><br />
<br><br><br />
<br />
'''T-Cell Acute Lymphoblastic Leukaemia'''<br><br />
T-cell acute lymphoblastic leukaemia (T-ALL) is an example of how abnormal Notch signalling can lead to the development of cancer. T-ALL is an aggressive childhood cancer of the immune system's T-cells. The NOTCH1 gene encodes the Notch1 receptor, which is involved in the determination of pluripotent cell progenitors to T-cells and the organisation of these cells in the developing thymus. Activating mutations in the extracellular domain and/or the C-terminal PEST domain of Notch1 have been identified in more than half of all cases of T-ALL.<ref><pubmed>15472075</pubmed></ref><br />
<br><br><br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Other Examples of Roles of Notch in Cancer <small>(adapted from ''Notch in disease''<ref name="PMID23729744"/>)</small><br />
|-<br />
|-bgcolor="a3bfb1"<br />
| '''Gene'''<br />
| '''Role of Notch'''<br />
| '''Disease'''<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br>''NOTCH2''<br />
| Oncogene<br>Tumour suppressor<br />
| Pancreatic ductal adenocarcinoma<br />
|-<br />
| ''NCSTN''<br>''MAML1''<br>''APH1A''<br>''NOTCH2''<br />
| Tumour suppressor<br />
| Chronic myelomonocytic leukaemia<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br />
| Oncogene<br />
| Chronic lymphocytic leukaemia<br />
|-<br />
| Activated NOTCH<br />
| Tumour suppressor<br />
| Hepatocellular carcinoma<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br>''NOTCH2''<br>''NOTCH3''<br />
| Tumour suppressor<br />
| Head and neck squamous cell carcinoma<br />
|-<br />
| NOTCH<br />
| Tumour suppressor<br />
| B-cell acute lymphoblastic leukaemia<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br />
| Oncogene<br />
| Non-small-cell lung cancer<br />
|-<br />
| ''NOTCH1''<br />
| Oncogene<br />
| T-cell acute lymphoblastic leukaemia<br />
|}<br />
<br><br />
<br />
====Quiz Your Notch-Knowledge on Abnormalities in Notch Signalling!====<br />
<br />
<quiz display=simple><br />
{ What is the name for the collection of rib and spine abnormalities that result from interruption in the Notch pathway that leads to inhibition of somite segmentation in the embryo?<br />
|type="()"}<br />
- &nbsp; Alagille Syndrome<br />
- &nbsp; T-cell acute lymphoblastic leukaemia<br />
+ &nbsp; Spondylocostal Dysostosis<br />
- &nbsp; CADASIL<br />
|| Remember, Spondylocostal Dysostosis is a collective term for conditions characterised by anomalies relating to rib and spine. Genetic changes lead to an interruption in the Notch pathway that inhibits the somite segmentation resulting in abnormalities relating to the ribs and spine. Alagille syndrome is an autosomal dominant, multisystem disorder that mainly affects the liver, heart, and kidney. T-cell acute lymphoblastic leukaemia is an aggressive childhood cancer of the immune system's T-cells. CADASIL is an autosomal-dominant disease of the small to medium-sized arteries, mainly in the brain, that leads to dementia and disability in mid-life.<br />
</quiz><br />
<br />
===Current Areas of Research and Future Directions===<br />
Notch has been identified as having a role in the development of several cancers, and therefore research has recently begun investigating the use of Notch inhibitors in cancer treatment.<ref>As reviewed by <pubmed>27732970</pubmed></ref> γ-secretase inhibitors (GSIs), which inhibit the normal cleavage of Notch at the cell membrane and hence NICD release, have been a popular area of research. In the specific case of desmoid tumours, it was observed that treatment GSIs resulted in decreases in NICD and Hes1 expression in the tumour cells. Overall, tumour cell migration and invasion were decreased and cell growth was also inhibited.<ref><pubmed>26349011</pubmed></ref> GSIs have also been shown to have an inhibitory growth effect on pancreatic, breast, and lung cancers, but unfortunately they also produce side effects ''in vivo''.<ref>As reviewed by <pubmed>27688721</pubmed></ref> Therefore continued study into GSIs is required to make them safe for human treatment. Ultimately, with ongoing research, it is possible that the Notch pathway will eventually become an effective therapeutic target for cancers.<br />
<br><br><br />
<br />
<big><b>To search and read recent PubMed research and review articles on Notch, click <u>[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=Notch here]</u>!</b></big><br />
<br><br><br />
<br />
===Want to Read More About Notch?===<br />
The [http://www.omim.org/ OMIM (Online Mendelian Inheritance in Man) database] contains extensive information about the Notch genes and associated proteins and is a great place to go if you want to find out more about the Notch pathway in humans! Click on these links to learn more about the Notch genes that encode the human receptors and ligands:<br />
<li>[http://www.omim.org/entry/190198 NOTCH1] | [http://www.omim.org/entry/600275 NOTCH2] | [http://www.omim.org/entry/600276 NOTCH3] | [http://www.omim.org/entry/164951 NOTCH4]<br />
<li>[http://www.omim.org/entry/601920 JAG1] | [http://www.omim.org/entry/602570 JAG2]<br />
<li>[http://www.omim.org/entry/606582 DLL1] | [http://www.omim.org/entry/602768 DLL3] | [http://www.omim.org/entry/605185 DLL4]<br />
<br><br><br />
<br />
You can also look at these papers for examples of reviews and research papers that reinforce the diversity of how the Notch pathway functions in organisms.<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch influences adult development as well!</big><br />
|-<br />
|Interestingly, Notch does not only play a role in human embryonic development, but has also been found to influence developmental processes after birth. One of these processes is neurogenesis, for example.<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159580/ '''Not(ch) just development: Notch signalling in the adult brain.'''] <br />
<br />
This review explains that the Notch signalling pathway, which is so often regarded as a major molecular player in development, actually has important functions related to neural cells in the adult. As you would have read in the [[#Abnormalities in Notch signalling| Abnormalities in Notch Signalling]] section, Notch abnormalities are involved in a number of diseases, which underlines its importance in maintaining adult brain function. Some highlights of this review are: Figure 2 provides a schematic representation of precise roles Notch activation can play in the adult brain; explanations of the ways that Notch influences brain plasticity; and the discussion of conflicting results of studies exploring the role of Notch in stroke recovery.<ref name=PMID21505516><pubmed>21505516</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch Modulation for Therapy</big><br />
|-<br />
|As you would have read in the [[#Abnormalities in Notch signalling| Abnormalities in Notch Signalling]] section, Notch can play different roles in cancer development. An interesting review further elucidates that modulation of Notch signalling is actually being investigated as a potential target for cancer therapy:<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704338/ '''Targeting the Notch signaling pathway in cancer therapeutics'''] <br />
<br />
This articles focuses on reviewing data emerging from recent research, explaining how Notch contributes to the development of a number of cancers, and then outlining the current focuses of investigations into how to therapeutically manipulate the Notch pathway. Some highlights from this review are: the detailed description of how Notch interacts with other signalling pathways such as Wnt and the signalling cytokine Interleukin-6; explanations of the seemingly conflicting roles of Notch as a tumour promoter and suppressor; and discussion of the findings of various Notch-related studies in cancer stem cells.<ref name=PMID26767041><pubmed>26767041</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch influences reproduction in worker honey bees!</big><br />
|-<br />
| In our [[#Roles in Animal Development| Roles in Animal Development]] section we discussed Notch in relation to a number of animals, however one that we did not cover was the worker honey bee, or ''Apis mellifera''. A recent study shows that Notch also plays a role in these honeybees!<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976197/ '''Notch signalling mediates reproductive constraint in the adult worker honeybee.'''] <br />
<br />
This research paper essentially concludes that in the worker honeybee Notch signalling constrains reproduction between males and females; they were the first team to elucidate a molecular mechanism underlying the link between adult ovary activity in bees and the presence of the queen bee. Some highlights from this unique and interesting study are: the background explanation that female worker bees have suppressed activity due to pheromones produced by the queen; the finding that Notch plays a part in this inactivation of reproductivity; and the discussion about social control of reproduction and evolution.<ref name=PMID27485026><pubmed>27485026</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch signalling is involved in embryo implantation!</big><br />
|-<br />
| Notch is essential for many developmental embryonic processes, as described in our [[#Roles in Embryonic Development|Roles in Embryonic Development]] section. Interestingly, research has shown that Notch signalling also has an important role in the initial process of establishing a successful pregnancy. Specifically, normal Notch signalling has been seen to be a critical factor in fetal-maternal communication during implantation and placentation. (To read more about these processes, go to these pages on [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Week_1_and_2_Development Weeks 1-2] and [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Week_3_Development Week 3] of development.)<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/24357662 '''Fetal-maternal communication: the role of Notch signalling in embryo implantation.''']<ref>As reviewed by <pubmed>24357662</pubmed></ref><br />
<br />
This review describes both human and animal studies of Notch signalling during pregnancy. It explains research of Notch signalling at the human blastocyst-maternal interface, and that Notch signalling has been observed in both the maternal endometrium and the blastocyst. Furthermore, Notch signalling is also important for the processes of implantation and placentation. Overall, the review summarises findings of Notch signalling in endometrial-trophectoderm interactions during the implantation, regulation of extravillous trophoblast invasion and spiral artery remodelling in the decidua, and angiogenesis in the placenta, as well as how abnormal Notch signalling is related with impaired placentation and pre-eclampsia.<br />
|}<br />
<br><br />
<br />
===Glossary===<br />
{| class="pretty table"<br />
|-<br />
| '''AER'''<br />
| 'Apical Ectodermal Ridge' is a structure that forms from the ectodermal cells at the distal end of each limb bud. The AER acts as a major signalling centre in order to ensure proper limb development.<br />
|-<br />
| '''Apoptosis'''<br />
| Programmed cell death which occurs in the development of many systems.<br />
|-<br />
| '''Calcification'''<br />
| The accumulation of calcium salts in body tissue. It normally occurs in the formation of bone, but abnormally calcium can be deposited in soft tissue causing it to harden.<br />
|-<br />
| '''Cardiogenic'''<br />
| From cardiogenesis - meaning formation of the heart.<br />
|-<br />
| '''Cardiomyocyte'''<br />
| The muscle cells (myocytes) that make up the cardiac muscle<br />
|-<br />
| '''Congenital'''<br />
| (Of a disease or physical abnormality) present from birth.<br />
|-<br />
| '''Craniofacial'''<br />
| Meaning relating to the cranium and the face.<br />
|-<br />
| '''Cyclin D1'''<br />
| A protein required for progression through the G1 phase of the cell cycle. Read more about it [https://en.wikipedia.org/wiki/Cyclin_D1 here], or see information on its encoding gene here: [http://omim.org/entry/168461 OMIM168461].<br />
|-<br />
| '''Endocardial'''<br />
| From endocardium - meaning the thin, smooth membrane which lines the inside of the chambers of the heart and forms the surface of the valves.<br />
|-<br />
| '''Endocrine'''<br />
| As in the endocrine system, refers to glands that secrete hormones or other substances directly into the blood.<br />
|-<br />
| '''Epithelium'''<br />
| The thin tissue that forms the outer layer of a body's surface and also lines the alimentary canal and other hollow structures.<br />
|-<br />
| '''Gastrulation'''<br />
| Describes the formative process of the formation of the trilaminar embryo containing the three germ layers.<br />
|-<br />
| '''Gliogenesis'''<br />
| The formation and development of glial cells (astrocytes, oligodendrocytes, Schwann cells, microglia).<br />
|-<br />
| '''Haematopoietic'''<br />
| From haematopoiesis - meaning the formation of blood cellular components<br />
|-<br />
| '''Haploinsufficiency'''<br />
| When a diploid organism has only a single functional copy of a gene (with the other copy inactivated by mutation), and so the total level of a gene product (a particular protein) produced by the cell is about half of the normal level.<br />
|-<br />
| '''Homeostasis'''<br />
| The ability to maintain a constant internal environment in response to environmental changes.<br />
|-<br />
| '''Ligand'''<br />
| A molecule that binds to a specific binding site on a protein (receptor).<br />
|-<br />
| '''Mef2C promoters'''<br />
| Myocyte-specific enhancer factor 2C is a transcription factor in the Mef2 family that is encoded by the gene ''MEF2C'' in humans ([https://omim.org/entry/600662 OMIM 600662]). This gene is involved in cardiac morphogenesis and myogenesis, as well as vascular development. It is thought to also possibly play a role in neurogenesis.<br />
|-<br />
| '''Mesenchymal'''<br />
| From mesenchyme - meaning a loosely organised, mainly mesodermal embryonic tissue which develops into connective and skeletal tissues, including blood and lymph.<br />
|-<br />
| '''Morphogenesis'''<br />
| Refers to the origin and development of morphological characteristics.<br />
|-<br />
| '''Myogenic'''<br />
| From myogenesis - meaning formation of muscle.<br />
|-<br />
| '''Myogenin'''<br />
| Also known as myogenic factor 4, this is a muscle-specific basic-helix-loop-helix transcription factor involved in the coordination of skeletal muscle development or myogenesis and repair.<br />
|-<br />
| '''Neural Crest'''<br />
| In vertebrate embryos, this is a transient structure that gives rise to most of the peripheral nervous system and to a number of non-neural cell types such as the smooth muscle cells of the cardiovascular system. <br />
|-<br />
| '''Neurogenic'''<br />
| From neurogenesis - meaning the formation of nervous tissue.<br />
|-<br />
| '''Neurulation'''<br />
| The folding process in vertebrate embryos whereby the neural plate transforms into the neural tube.<br />
|-<br />
| '''NICD'''<br />
| Notch intracellular domain<br />
|-<br />
| '''Oncogenic'''<br />
| From oncogenesis, also known as tumorigenesis or carcinogenesis - meaning the formation of a cancer, whereby normal cells are transformed into cancer cells.<br />
|-<br />
| '''Paracrine'''<br />
| A hormone that exerts an effect only in the vicinity of the gland secreting it.<br />
|-<br />
| '''Protease'''<br />
| An enzyme which breaks down proteins and peptides.<br />
|-<br />
| '''Runx2'''<br />
| Runt-related transcription factor 2 is a protein that in humans is encoded by the ''RUNX2'' gene ([http://omim.org/entry/600211 OMIM600211]). RUNX2 is an important transcription factor associated with osteoblast (bone substance-secreting cells) differentiation.<br />
|-<br />
| '''Stromal cells'''<br />
| The connective tissue cells of any organ. They support the function of the parenchymal cells of that organ. Fibroblasts and pericytes are among the most common types of stromal cells.<br />
|-<br />
|}<br />
<br />
====Further Glossary Links====<br />
[[A|A]] | [[B|B]] | [[C|C]] | [[D|D]] | [[E|E]] | [[F|F]] | [[G|G]] | [[H|H]] | [[I|I]] | [[J|J]] | [[K|K]] | [[L|L]] | [[M|M]] | [[N|N]] | [[O|O]] | [[P|P]] | [[Q|Q]] | [[R|R]] | [[S|S]] | [[T|T]] | [[U|U]] | [[V|V]] | [[W|W]] | [[X|X]] | [[Y|Y]] | [[Z|Z]] | [[Numbers|#]]<br />
<br />
===References===<br />
<references/></div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=2016_Group_Project_2&diff=255168
2016 Group Project 2
2016-10-27T08:03:43Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016header}}<br />
{{Group Assessment Criteria table}}<br />
<!-- Do not delete the above template from the Group project page. --><br />
=The Notch Signalling Pathway=<br />
===Introduction===<br />
The Notch signalling pathway is the most prevalent form of intracellular communication in multicellular organisms. It is a critical pathway for cell differentiation, proliferation, and apoptosis. It is involved in embryonic organ development through the regulation of cell-cell signalling; specifically lateral inhibition, formation of boundaries, and cell lineage assignation.<ref name="The Developing Human">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2015). The developing human: clinically oriented embryology (10th ed.). Philadelphia: Saunders.</ref><ref name="PMID10075488">As reviewed by <pubmed>10075488</pubmed></ref> This pathway is also actively involved in adjacent cell communication, developmental process such as adult homeostasis, and stem cell maintenance. Since this pathway is an intricate and crucial aspect of an organism's development and cell signalling, a mutation in the functional components of this pathway can cause a myriad of diseases such as congenital disorders, cancers, strokes, Alagille syndrome, and leukoencephalopathy.<ref name="PMID19255248">As reviewed by <pubmed>19255248</pubmed></ref> The process of Notch signalling primarily utilises a ligand-receptor interaction to release protein fragments at the cellular membrane, which then provide signals to the internal environment of the cell and to adjacent cells. In mammals, the Notch signalling pathway is comprised of four receptors (Notch 1-4) which interact with Delta or Jagged ligands to bring about the activation of this pathway. Homologous Notch genes have been identified in other animals, such as ''Drosophila melanogaster'' (fruit fly) and ''Danio rerio'' (zebrafish).<br />
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<big>What will you find on this wiki page?</big><br />
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This page is designed to provide an overview of such features of the Notch signalling pathway, but is in no way a complete resource for all Notch-related information (especially since this signalling pathway has such a wide array of activities in many organisms and the scientific understanding of it is continuously updating!). By reading this page you should come to a better understanding of Notch in regards to: general molecular mechanisms; embryonic development by systems; examples of animal development; abnormalities and disease; current and potential future research; as well as a couple of links to interesting articles for those who want to read more. There is a [[#Glossary| Glossary]] at the bottom of the page for better understanding of scientific terms used throughout this page, and readers are encouraged to 'expand' any collapsed information on the page to optimise their experience in reading about Notch. <br />
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<div align="center"><html5media width="560" height="315">https://www.youtube.com/embed/axkDX0XZyN0</html5media></div><br />
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===History===<br />
{| class="pretty table"<br />
|-bgcolor="FAF5FF" <br />
| 1914<br />
| First description of a "notch" defect (loss of tissue in the wing) in ''Drosophila'' by John S. Dexter, giving the gene its name<ref>Dexter, J. (1914). The Analysis of a Case of Continuous Variation in Drosophila by a Study of Its Linkage Relations. ''The American Naturalist'', 48(576), 712-758. Retrieved from http://www.jstor.org/stable/2455888</ref><br />
|-<br />
| 1917<br />
| First allele of ''Notch'' is identified by Thomas Hunt Morgan<ref>Morgan, T. H. (1917). The theory of the gene. ''The American Naturalist'', 51(609), 513-544.</ref><br />
|-bgcolor="FAF5FF" <br />
|-<br />
| 1930s<br />
| Donald F. Poulson conducts research into the involvement of ''Notch'' in development.<ref><pubmed>16588136</pubmed></ref> <br />
|-<br />
| 1958<br />
| An investigation by W.J. Welshons confirmed that the locus of Notch is contained within the 3C7 band of the X chromosome.<ref><pubmed>13635554</pubmed></ref><br />
|-bgcolor="FAF5FF" <br />
|-<br />
| 1983<br />
| DNA sequences belonging to the Notch locus cloned and determined that RNA is required for the function of the wild type Notch. Further insight developed into the function of Notch and its role in differentiation and regeneration.<ref><pubmed>6403942</pubmed></ref><br />
|-<br />
| 1986<br />
| The molecular analysis and sequence of the Notch locus was determined by Michael W. Young and his team. A relationship was identified between the protein encoded by the major Notch transcript and mammalian clotting and growth factors.<ref><pubmed>3097517</pubmed></ref><br />
|-bgcolor="FAF5FF" <br />
| 1989<br />
| Neurogenic loci "Delta" and "Mastermind" identified and research conducted to search for genes which may have an interaction with the Notch protein. It was confirmed that mutations in these loci will affect neurogenesis.<br />
|}<br />
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===Overview of Molecular Mechanisms===<br />
Mammals possess a total of four ''Notch'' genes, with five genes for encoding the associated ligands, Delta-like and Jagged. The ''Notch'' genes each code for a single transmembrane receptor. Extracellularly, it contains epidermal growth factor (EGF)-like repeats for ligand interaction and Lin-12-Notch (LN) repeats for regulating the interactions between the extracellular and intracellular regions. Intracellularly, Notch has seven ankyrin (ANK) repeats and a transactivation domain (TAD), as well as a proline, glutamine, serine, threonine-rich (PEST) domain for degradation of Notch.<br />
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[[File:Notch structure cartoon.jpg|thumb|700px|center|'''The structure of the Notch receptor.'''<ref name="PMID19255248"/> Extracellularly there are epidermal growth factor (EGF)-like repeats and Lin-12-Notch repeats (LNRs). The Notch intracellular domain (NICD) is made up of a rRBP-Jkappa-associated module (RAM) domain, ankyrin (ANK) repeats, and a proline, glutamine, serine, threonine-rich (PEST) domain. There are three sites for cleavage by enzymes: S1, S2, and S3/S4.]]<br />
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====Canonical pathway====<br />
[[File:Overview of Notch signalling.png|thumb|500px|'''Summary of canonical Notch signalling.''' The interaction between Delta-like or Serrate ligands (DSL) and the Notch receptor on an adjacent cell initiates proteolytic cleavage of Notch and the release of the Notch intracellular domain (NICD). The NICD is then transported to the nucleus where it can induce transcription of Notch target genes by binding to specific proteins (MAM, CSL).<ref><pubmed>27404588</pubmed></ref>]]<br />
The canonical Notch pathway is unique in that it involves direct interaction between adjacent cells, as opposed to paracrine signalling, because both the Notch ligands and Notch receptors are transmembrane proteins found in the cell membrane. Furthermore, the lack of a secondary messenger or amplification process means that the Notch pathway has limited opportunities for regulation and must therefore be tightly controlled. Depending on its developmental and cellular context, activation or inhibition of the pathway can result in a variety of cellular responses, including cell death, proliferation, or differentiation.<ref name="Introduction to Notch Signalling">Yamamoto, S., Schulze, K.L. & Bellen, H.J. (2014). Introduction to Notch Signalling. ''Notch Signaling: Methods and Protocols''. Methods in Molecular Biology: 1187</ref><br />
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Four Notch proteins are involved in the canonical pathway. NOTCH1 to NOTCH4 are single transmembrane receptors and can interact with a variety of ligands, including NOTCH ligands (e.g. Delta ligands) and Serrate ligands. There are three Delta ligands (Dll1, Dll3, and Dll4) and two Serrate ligands (Jagged1 and Jagged2) present in mammals.<ref name="Introduction to Notch Signalling"/> The binding between the Notch receptor and the ligand on the adjacent cell induces the release of the Notch intracellular domain (NICD) via a sequence of proteolytic reactions.<ref name="The Developing Human"/> Cell-cell interaction is therefore critical in the process of triggering Notch signalling.<br />
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The interaction on the cell surface between Notch and its ligand on an adjacent cell causes the extracellular metalloprotease site (S2 site) to be exposed. The S2 site is then cleaved by transmembrane proteases belonging to the a disintegrin and metalloproteinase/tumour necrosis factor α converting enzyme (ADAM/TACE) family. The remaining Notch fragment subsequently undergoes two more intramembranous cleavages at the S3/S4 sites by the γ-secretase complex. Finally, the NICD is released and enters the nucleus to interact with CSL (CBF1, Suppressor of Hairless, Lag-1) and Mastermind-like proteins (MAMLs). CSL is a DNA-binding protein that acts as a transcription factor by forming repressor or activator complexes; in the absence of the NCID, CSL is bound to corepressor proteins (CoR) that prevent transcription of Notch target genes. MAMLs are transcriptional co-activators that are required for transcription of the target genes, hence they are involved in the regulation of the pathway.<ref name=PMID10075488/><ref name="Introduction to Notch Signalling"/> To stop signalling, the NICD is phosphorylated by kinases and ubiquitinated by E3 ubiquitin ligases, which results in proteasome mediated degradation and subsequent termination of the signal.<ref name="Introduction to Notch Signalling"/><br />
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====Non-canonical pathway====<br />
Immense research has been carried out on the canonical Notch pathway and its members are well known. While canonical notch ligands control most of the known Notch signalling, a group of structurally distinct non-canonical ligands exist which activate Notch and its pleiotropic effects. Notch can non-canonically carry out its functions by post-translationally targeting Wnt/β-catenin signalling. This type of signalling is CSL-independent and can also work independently of ligands. Some genes are affected by the non-canonical Notch signalling, however their mediators in most cases are unknown. Notch binds and titrates levels of active β-catenin. Therefore, active β-catenin activity may serve as a useful readout for non-canonical Notch signals.<ref name="PMID22397947">As reviewed by <pubmed>22397947</pubmed></ref> <br />
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Recent research has shown that Notch signalling plays crucial roles for cellular differentiation during development through γ-secretase-dependent intramembrane proteolysis followed by transcription of target genes. Hayashi et al. (2016) uncovered a ligand-dependent but γ-secretase-independent, non-canonical Notch signalling involved in presynaptic protein expression in postmitotic neurons.<ref name="PMID27040987"><pubmed>27040987</pubmed></ref><br />
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====Transcriptional regulation of Notch signalling====<br />
A number of genes have been found to act as modulators of Notch signalling by modifying the ability of Notch to interact with its ligands. These include proteins acting extracellularly (Fringe, Brainiac, Egghead, Scabrous, Wingless), proteins acting at the cell membrane (Big brain), proteins acting intracellularly (Numb, Sanpodo, Disabled, Deltex, Dishevelled), and proteins acting within the nucleus (Hairless, EMB-5, Strawberry notch).<ref name="PMID9892565">As reviewed by <pubmed>9892565</pubmed></ref><br />
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In ''Drosophila melanogaster'', it has been seen that ''fringe'' is able to affect the ability of Notch to be activated by the Serrate and Delta ligands. Specifically in the ''Drosophila'' wing, it was observed that Serrate did not interact with Notch in specific areas due to the action of ''fringe''<ref><pubmed>9247339</pubmed></ref>. Fringe is not required for initial Notch signalling, but is thought to be important for signalling processes when Notch activation occurs along the borders between distinct cell populations. Research suggests that Fringe specifically affects the binding between Notch and its ligands, rather than an activation step separate or subsequent to ligand binding. The ''brainiac'' and ''egghead'' genes are thought to either influence the production of a Notch ligand or act as substitute ligands themselves.<ref name="PMID9892565"/><br />
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====Examples of Proteins Involved in Interaction with the Notch Intracellular Domain <small>(adapted from Table 3<ref name="PMID21828089"/>)</small>====<br />
{| class="pretty table"<br />
|-bgcolor="A3BFB1" <br />
| '''Protein'''<br />
| '''Interaction with NICD'''<br />
|-bgcolor="F5FFFA"<br />
| Adenamatous polyposis coli (Apc)<br />
| Controls Notch trafficking<br />
|-<br />
| Cyclin-dependant kinase 8 (CDK8)<br />
| Phosphorylates NICD to make it a substrate for ubiquitylation and degradation<br />
|-bgcolor="F5FFFA"<br />
| CBF1, Su(H) and LAG-1/Recombination signal binding protein for immunoglobulin kappa J region (CSL/RBP-J)<br />
| Main canonical transcriptional co-factor for NICD<br />
|-<br />
| Cyclin C (CycC)<br />
| Targets NICD for phosphorylation to make it a substrate for ubiquitylation and degradation<br />
|-bgcolor="F5FFFA"<br />
| Dishevelled (Dsh/Dvl)<br />
| Controls ligand-independent Notch trafficking; inhibits canonical Notch signalling<br />
|-<br />
| Deltex-1-4 (Dtx1-4)<br />
| Controls Notch ubiquitylation, processing, and internalisation<br />
|-bgcolor="F5FFFA"<br />
| Itchy, E3 ubiquitin protein ligase (Itch)<br />
| Promotes ubiquitylation of NICD<br />
|-<br />
| Mastermind-like 1/2 (Maml1/2)<br />
| Co-activator for NICD/CSL<br />
|-bgcolor="F5FFFA"<br />
| Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-ϰb)<br />
| NICD blocks NF-ϰb transcription of NF-ϰb target genes through binding to p50/cRel<br>NICD enhances NF-ϰb transcription of target genes by retaining NF-ϰb in the nucleus<br />
|-<br />
| Numb homolog (Numb)<br />
| Suppresses Notch signaling by recruiting E3 ubiquitin ligases to ubiquitylate Notch<br>Controls Notch trafficking during asymmetric cell division<br />
|-bgcolor="F5FFFA"<br />
| Smad family members (SMAD)<br />
| Smads enhance Notch signalling; Notch fine-tunes signalling through Smads<br />
|}<br />
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===Roles in Embryonic Development===<br />
The phylogenetically conserved Notch signalling pathway plays a crucial role in the development of multiple organ systems, and is a major regulator of stem cell fate. It is responsible for the regulation of the transcription of a number of signalling molecules, such as ''MyoD'', ''Mash1'' and ''GATA2'', which are genes controlling the fate of myogenic, neurogenic and haematopoietic stem cells, respectively. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> The following subsections will further elucidate the vital roles of Notch signalling during normal embryonic development. If you would like to better understand human embryonic development before reading this section, [https://embryology.med.unsw.edu.au/embryology/index.php/Embryonic_Development| this page] serves as a great resource. <br />
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====Cardiovascular====<br />
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If you would like to generally learn about and become familiar with cardiac development in the embryo before reading this section, click [https://embryology.med.unsw.edu.au/embryology/index.php/ANAT2341_Lab_11_-_Heart here]!<br />
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'''Cardiomyocyte Specification and Differentiation'''<br />
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Expression during the appropriate window of the timeline of embryogenesis of Notch receptors, ligands and downstream effector molecules elucidates a role for the Notch pathway in the earliest stages of cardiac development. It has been found to restrict the expression of specific cardiogenic genes in a spatiotemporal manner and regulate cardiac field specification as early as during gastrulation. <ref name=PMID19580804><pubmed>19580804</pubmed></ref> Interestingly, Notch has been found to play both suppressive and promoting roles in cardiogenesis.<br />
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For example, it has been shown that Notch suppresses cardiomyocyte cell fate specification during early cardiogenesis. This has been demonstrated through studies such as that carried out by Rones and colleagues (2000), which used activation and inhibition of Notch signaling in Xenopus. <ref name=PMID10934030><pubmed>10934030</pubmed></ref><br />
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On the other hand, studies such as that by Boni et al. (2008) have found that Notch signalling may also promote myogenesis from cardiac progenitor cells. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> Cardiogenesis has also been promoted by downregulating Notch-1 activity in stem cells of embryos (Nemir et al., 2006).<ref name=PMID16690879><pubmed>16690879</pubmed></ref><br />
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Despite the understanding that Notch signalling is crucial to embryonic myogenesis, the exact molecular mechanism remains elusive. Research by Buas and colleagues (2010) has explored such mechanisms by studying the Notch target, Hey1, which is known to suppress myogenic differentiation. They concluded that this inhibitory function of Hey1 is primarily mediated through binding near to myogenin and Mef2C promoters, which leads to cessation of target gene expression. <ref name=PMID19917614><pubmed>19917614</pubmed></ref><br />
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[[File:Notch CVS simple diagram.png|thumb|500px|right|alt=Simplified Scheme of the Roles of Notch in Cardiac Development|'''Simplified Scheme of the Roles of Notch in Cardiac Development.''' Notch has been found to restrict the expression of specific cardiogenic genes in a spatiotemporal manner and regulate cardiac field specification early in development. Further after cardiac differentiation, Notch influences development of the AVC (atrioventricular canal), cardiac valves, ventricular trabeculae and the cardiac outflow tract. (This student-drawn image is based upon Figure 2 in the 2014 review by Zhou and Liu: [https://www.ncbi.nlm.nih.gov/pubmed/24345875 ''Role of Notch signaling in the mammalian heart.'']<ref name=PMID24345875><pubmed>24345875</pubmed></ref>)]]<br />
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'''Development of the Atrioventricular Canal'''<br />
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A study by Rutenberg et al. (2006) and another by Kokubo et al. (2007) implicate a role for Notch signaling in the region between the atria and the ventricles of the heart (the atrioventricular canal, or AVC).<ref name=PMID17021042><pubmed>17021042</pubmed></ref> <ref name=PMID17259303><pubmed>17259303</pubmed></ref> They used chicken and mouse models, respectively, to show that other signalling factors, ''Bmp2'' and ''Tbx2'', are restricted to the AVC region by Notch signalling during development. <br />
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Furthermore, Watanabe and colleagues (2006) showed that deletion of Notch targets increases ''Bmp2'' expression and expansion of the AVC tissue, however other, non-Notch restrictive factors involved in AVC development are likely to exist.<ref name=PMID16554359><pubmed>16554359</pubmed></ref> <br />
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'''Heart Valve Development'''<br />
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In order for the heart valve to properly form in the embryo, endocardial to mesenchymal transformation (EMT) must occur. The Notch pathway, alongside Wnt and Bmp, has been found to regulate the process of EMT, defects in which can lead to congenital heart valve disease. Interestingly, Timmerman and colleagues (2004) demonstrated that this role of Notch may also promote oncogenic transformation. This team also showed that embryos exhibited abortive endocardial EMT if they were deficient in Notch signalling components in vivo and in vitro. <ref name=PMID14701881><pubmed>14701881</pubmed></ref> <br />
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A more recent paper by Wang et al. (2013) further explored the underlying signalling processes and interrelationships of molecules that impact EMT. They found that Jagged1-Notch1 signalling in cells of the endocardium potentiates expression of Wnt4, which in turn carries out paracrine action on adjacent AVC tissue to upregulate Bmp2 expression and thus signal EMT. <ref name=PMID23560082><pubmed>23560082</pubmed></ref><br />
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'''Trabeculation'''<br />
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Trabeculation is the initial process of ventricular chamber development that forms a series of cardiomyocyte projections within the lumens of the ventricles of the heart (called trabeculae). Grego-Bessa and colleagues (2007) addressed the roles Notch plays in trabeculation through ''RBPJk'' (the gene product of which interacts with Notch) and ''Notch1'' gene manipulation. Mutants of these two genes showed perturbed expression and signalling of ''EphrinB2'', ''NRG1'' and ''BMP10'', alongside reduced proliferation of myocardiocytes. This research ultimately suggested that ''EphrinB2'' is a direct target of Notch in the endocardium that simultaneously requires the Notch-dependent action of BMP10 and NRG1 in order for ventricular myocardium proliferation and differentiation to occur normally. <ref name=PMID17336907><pubmed>17336907</pubmed></ref> Furthermore, the important process of trabeculation has recently been shown to be controlled by sequential Notch activation by an investigation by D’Amato et al. (2015). <ref name=PMID26641715><pubmed>26641715</pubmed></ref><br />
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'''Development of the Outflow Tract'''<br />
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About one third of congenital heart defects include malformations in the outflow tract which include the aorta, pulmonary arteries, aortic arch and ductus arteriosus. During cardiogenesis, neural crest cells interact with second heart field myocardium and endocardial mesenchyme. <ref><pubmed>20201902</pubmed></ref> <br />
Studies involving neurogenesis demonstrated the sensitivity of Notch signaling to temporal and spatial cues and showed the early Notch signaling initially controls the number of cells with a neurogenic fate and later dictates the lineage decision of neural versus glial cell fate. <ref><pubmed>16429119</pubmed></ref><br />
Neural crest precursors for ideal patterning of the outflow tract are required in the Notch signaling pathway. The use of a dominant negative form of a master mind like protein (MAML) which has shown to be a pan Notch inhibitor in neural crest cells inactivates Notch signaling. This results in congenital heart defects like pulmonary artery stenosis and aortic arch patterning defects associated with defects in smooth muscle formation. <ref><pubmed> 17273555 </pubmed></ref><br />
Part of the phenotype in defective neural crest cells is attributed to loss of Notch2 signalling as Notch2 inactivation in these cells produces small caliber aortas and pulmonary arteries because of defects in smooth muscle. <ref><pubmed> 18330927 </pubmed></ref><br />
Jagged1 is the ligand involved which signals to Notch on neural crest cell surfaces to induce vascular smooth muscle cell differentiation. <ref><pubmed> 18245384 </pubmed></ref><br />
Mutations in both JAGGED1 and NOTCH2 genes have been known to cause Alagille syndrome, further substantiating the importance of this pathway in proper formation of the outflow tract. <ref><pubmed> 16575836 </pubmed></ref><br />
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Another study by Garg stresses the importance of Notch signaling in the outflow tract region. NOTCH1 mutations were seen in patients with aortic stenosis. Aortic stenosis results from the calcification of the aortic valve and is quite common in adults. However, in children, this may result in failure of the left ventricle to develop properly. NOTCH1 haploinsufficiency is also linked to early calcification and bicuspid aortic valve disease. This could be due to an early induction of Runx2 through the HRT genes.<br />
<ref><pubmed> 16025100 </pubmed></ref><br />
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====Central Nervous System====<br />
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If you would like to generally learn about and become familiar with neural development in the embryo before reading this section, click [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Neural_Development here]!<br />
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[[File:Notch CNS simple diagram.png|thumb|450px|right|alt=Simplified Diagram of Roles of Notch in Neuronal Differentiation|'''Simplified Diagram of Roles of Notch in Neuronal Differentiation'''. Notch influences the differentiation of embryonic stem cells into neural cells via signalling with RBP (recombining binding protein), cyclin D1 and Hes1. (This student-drawn image is based upon Figure 1 from Chuang, Tung and Lin's 2015 review: [https://www.ncbi.nlm.nih.gov/pubmed/25815127 ''Neural differentiation from embryonic stem cells in vitro: An overview of the signaling pathways'']<ref name="PMID25815127"><pubmed>25815127</pubmed></ref>)]]<br />
'''Early Neural Differentiation'''<br />
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Notch plays a major role in promoting neural commitment of cells. Lowell and colleagues (2011) used genetic manipulation to discover that the phenotype of stem cells is not affected by constitutively activated Notch in mouse embryonic stem cells (mESCs), however, interfering with Notch signalling -for example by pharmacological means- did impede neural fate determination. This role required Notch signalling via fibroblast growth factor (FGF) receptors. Furthermore, the conservation of the Notch signalling pathway within pluripotent stem cells is implied due to the existence of Notch ligands in stromal cells in human embryonic stem cells (hESCs) that induce neural differentiation. <ref name=PMID16594731><pubmed>16594731</pubmed></ref><br />
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Das and colleagues (2010) manipulated Notch protein levels during specific stages of neural differentiation and found that if Notch signalling pathways were activated during day 3 of neural development for 6 hours, cell proliferation was dramatically enhanced. This was attributed to the induction by Notch of cyclin D1 expression. Without Notch signalling during neural development, there was reduced cyclin D1 levels. Manipulation of mESCs to express a dominant negative form of cyclin D1 resulted in abrogation of cell proliferation stimulated by Notch. Overall these results imply a temporally-specific role for Notch in CNS development, and that it requires cyclin D1 as a signalling molecule.<ref name=PMID20887720><pubmed>20887720</pubmed></ref><br />
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Hes1 has also been shown to play a Notch-mediated role in neural progenitor maintenance, which is essential for proper development since cells need to proliferate only during specific periods in the embryo for the correct number, cell type and function to result. Shimojo, Ohtsuka and Kageyama (2008) used real time imaging in mice to show that Notch induces oscillatory expression of ''Hes1'' and other Notch target genes to maintain the complex temporal organisation of events in neural development. They concluded that further research could elucidate more about Hes1 oscillations in regards to neural progenitor maintenance, proliferation and differentiation <ref name=PMID18400163><pubmed>18400163</pubmed></ref>.<br />
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Lastly, as well as influencing neural progenitor differentiation, it has been found that Notch also impacts the development and maintenance of polarised neural structures in the embryo. This was concluded from a knockout study in mice that elucidated a role for RBP (recombining binding protein), downstream of Notch, in modulating neural differentiation and maintaining rosette structure (an experimental ''in vitro'' correlate used for neural tube development) <ref name=PMID23675446><pubmed>23675446</pubmed></ref>. The researchers concluded that RBP knockouts lacked canonical Notch signalling and as a result showed multiple neurulation defects.<br />
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====Other Systems====<br />
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As aforementioned, Notch plays a wide array of roles in embryonic development, the follow table summarises these roles by each organ system:<br />
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<big>Summary Table of Examples of Notch Signalling in Developmental Processes</big> <small>(adapted from Table 1<ref name="PMID21828089">As reviewed by <pubmed>21828089</pubmed></ref>)</small><br />
{| class="pretty table"<br />
|-bgcolor="CEDFF2"<br />
| '''Organ/Tissue'''<br />
| '''Processes regulated by Notch'''<br />
|-bgcolor="F5FAFF" <br />
| Brain<br />
| Controls the balance between gliogenesis and neurogenesis; stem cell maintenance<ref><pubmed>21262462</pubmed></ref><ref>As reviewed by <pubmed>20816397</pubmed></ref>; organisation and maintenance of polarity during early development<ref name="PMID23675446"/><br />
|-<br />
| Craniofacial structures<br />
| Palate morphogenesis: loss of Notch signalling results in cleft palate, fusion of the tongue with the palatal shelves, and other craniofacial defects; also involved in tooth development<br />
|-bgcolor="F5FAFF"<br />
| Ear<br />
| Defines the presumptive sensory epithelium; determines hair cell and supporting cell fates<br />
|-<br />
| Esophagus<br />
| Regulates esophageal epithelial homeostasis<br />
|-bgcolor="F5FAFF"<br />
| Heart<br />
| Cardiac patterning, cardiomyocyte differentiation, valve development, ventricular trabeculation, outflow tract development<br />
|-<br />
| Intestine<br />
| Controls proliferation and differentiation, including absorptive vs. secretory cell fates<br />
|-bgcolor="F5FAFF"<br />
| Limbs<br />
| Apical ectodermal ridge (AER) formation and digit morphogenesis, especially regulation of apoptosis<br />
|-<br />
| Lungs<br />
| Lateral inhibition between tracheal cells prevents extra cells from assuming the lead position during tracheal branching morphogenesis<br />
|-bgcolor="F5FAFF"<br />
| Neural crest<br />
| Controls patterning of neural crest precursors for the outflow tract region of the heart; regulates the transition from Schwann cell precursor to Schwann cell, controls Schwann cell proliferation and inhibits myelination; controls melanocyte stem cell maintenance<br />
|-<br />
| Pancreas<br />
| Specifies endocrine cell differentiation through lateral inhibition: endocrine lineage cells inhibit endocrine differentiation of their neighboring cells; maintains pancreatic endocrine precursor cells, inhibits terminal acinar cell differentiation; controls pancreatic epithelium branching and bud size<br />
|-bgcolor="F5FAFF"<br />
| Skin<br />
| Regulates cell adhesion, control of proliferation, hair follicle or feather papillae differentiation and homeostasis<br />
|-<br />
| Thyroid<br />
| Regulates the numbers of thyrocyte and C-cell progenitors and regulates differentiation and endocrine function of thyrocytes and C-cells<ref><pubmed>21364918</pubmed></ref><br />
|-bgcolor="F5FAFF"<br />
| Vasculature<br />
| Regulates arteriovenous specification and differentiation in endothelial cells and vascular smooth muscle cells; regulates blood vessel sprouting and branching<br />
|}<br />
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====Quiz Your Notch-Knowledge on Embryonic Development!====<br />
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<quiz display=simple><br />
<br />
{ In the development of which organ does Notch exert lateral inhibition to differentiate endocrine cells?<br />
|type="()"}<br />
- &nbsp; The heart<br />
- &nbsp; The central nervous system<br />
- &nbsp; The skin<br />
+ &nbsp; The pancreas<br />
|| Remember, Notch signals endocrine lineage cells of the developing pancreas to inhibit endocrine differentiation of their neighbouring cells, known as lateral inhibition. Notch plays various roles in the heart, central nervous system and skin, but not in this way. <br />
</quiz><br />
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===Roles in Animal Development===<br />
The Notch signalling pathway doesn't just play a significant role in human development, but also affects events such as neurogenesis and myogenesis in some animals (thus why these animals are often used as models for human development in research!). Read below for information on some of these roles for Notch.<br />
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[[File:Notch animals.png|thumb|450px|right|alt=Animals Whose Developmental Processes are Affected by Notch.|'''Animals Whose Developmental Processes are Affected by Notch.''' This is a simplified representation of a few examples of the animals (Drosophila flies<ref name=PMID21447553><pubmed>21447553</pubmed></ref>, C. elegans<ref name=PMID18599512><pubmed>18599512</pubmed></ref>, and the zebrafish<ref><pubmed>23840804</pubmed></ref>) in which development is influenced by the Notch signalling pathway, and their scientific names.]]<br />
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====''Drosophila melanogaster''====<br />
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'''(The Fly)'''<br />
<br />
Unlike the four Notch paralogs in humans, only one Notch homolog is present in ''Drosophila''.<ref name="Introduction to Notch Signalling"/><br />
<br />
Both canonical and non-canonical Notch signalling are involved in the structural and physiological responses and functional plasticity of olfactory receptor neurons in reaction to prolonged odour exposure.<ref><pubmed>26986723</pubmed></ref><ref><pubmed>26011623</pubmed></ref> Research has also shown that Notch is crucial for the formation of longitudinal connections in the Drosophila CNS. Kuzina, Song, and Giniger (2011) created temperature-sensitive mutations of Notch genes that prevented the development of mature longitudinal axon tracts. Additionally, it was found that the Notch phenotype appears at the earliest stages of the development of longitudinal connections in the CNS by observing early stage 13 embryos.<ref name=PMID21447553><pubmed>21447553</pubmed></ref><br />
<br><br><br />
<br />
====''Caenorhabditis elegans''====<br />
<br />
'''(The Worm)'''<br />
<br />
The Notch pathway in ''C. elegans'' occurs throughout development in populations of equipotent cells for neuronal function in postmitotic differentiated neurons. In these postmitotic neurons, there is a specialised post-embryonic development stage knows as 'dauer'. The Notch pathway is activated when cell signalling downstream of the developmental decision enter dauer. The Notch receptor glp-1 and the ligand lag-2 are expressed in the dauer stage and aid in maintaining this stage. Another Notch receptor, lin-12, functions upstream of insulin signalling components to promote conditions for growth and enhance dauer recovery. <ref name=PMID18599512><pubmed>18599512</pubmed></ref><br />
<br><br><br />
<br />
====''Danio rerio''====<br />
<br />
'''(The Zebrafish)'''<br />
<br />
The expression of Notch in the myogenic region and apical ectodermal ridge (AER) of the developing zebrafish fin is similar to what has been observed in developing chicken and mouse limbs, which shows how highly conserved the role of Notch signalling is in the development of appendages in vertebrates. During zebrafish embryogenesis, the timing and positioning of fin formation are dependent on Notch signalling. Notch is also involved in the actual processes of fin formation, such as AER signalling, chondrogenic differentiation, and myogenesis. In zebrafish embryos with defective Notch signalling, it was observed that the skeletal muscle fibres were thin and fragmented and the structure of the sarcomeres was significantly compromised. <ref name="PMID23840804"><pubmed>23840804</pubmed></ref><br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Expand this for an image from this research study</big><br />
|-<br />
|[[File:Abnormal pectoral fins are formed in Notch signalling disrupted larvae.jpg|thumb|450px|right|alt=Abnormal pectoral fins are formed in Notch signalling disrupted larvae|'''Abnormal pectoral fins are formed in Notch signalling disrupted larvae.''' (A–F) Live pictures of 5 dpf larvae. (A’) A pectoral fin from a sibling embryo showing the cartilaginous endoskeletal disc with individualized cells surrounded by thin matrix deposits, the fin fold and the chleitrum (n = 17) (E, E’). A similar pectoral fin was found in a DMSO-treated embryo (n = 9). Pectoral fins of Notch signalling disrupted embryos such as mibta52b (n = 18) (B, B’), jagged2 (n = 10) (C, C’) and Su(H)1+2 (n = 12) (D, D’) morphants and DAPT-treated embryos (n = 10) (F, F’) showing disorganized endoskeletal disc cells. cl, chleitrum; ed, endoskeletal disc; ff, fin fold.<ref name="PMID23840804"/>]]<br />
|}<br />
<br><br><br />
<br />
====Quiz Your Notch-Knowledge on Animal Development!====<br />
<br />
<quiz display=simple><br />
<br />
{In which animal (as described in this section) has it been shown that defective notch signalling leads to thinning and fragmentation of skeletal muscle fibres?<br />
|type="()"}<br />
- &nbsp; Drosophila melanogaster<br />
- &nbsp; I don't know!<br />
- &nbsp; Caenorhabditis elegans<br />
+ &nbsp; Danio rerio<br />
|| Remember, it was observed in one study that the skeletal muscle fibres of zebrafish (Danio rerio) were thin and fragmented and the structure of their sarcomeres were significantly compromised.<ref><pubmed>23840804</pubmed></ref> <br />
</quiz><br />
<br />
===Summary of Functions of Proteins Involved in Notch Signalling <small>(adapted from Table 1<ref name="PMID17761886"><pubmed>17761886</pubmed></ref>)</small>===<br />
{| class="pretty table"<br />
|-bgcolor="a3bfb1"<br />
| '''Mammals'''<br />
| '''''Drosophila'''''<br />
| '''''C.elegans'''''<br />
| '''Function'''<br />
|-bgcolor="F5FFFA" <br />
| Notch 1-4<br />
| Notch<br />
| Lin-12, Glp-1<br />
| Single transmembrane receptor and transcription factor<br />
|-<br />
| Delta 1, Delta3-4, Jagged1-2<br />
| Delta, Serrate<br />
| APX-1, LAG-2, ARG-1, DSL-1<br />
| Single transmembrane ligands of the Notch receptor<br />
|-bgcolor="F5FFFA" <br />
| CBF1/RBPJK<br>Mastermind1-3<br />
| Su(H)<br>Mastermind<br />
| Lag-1<br>Lag-3<br />
| DNA-binding transcription factor<br>Transcriptional co-activator<br />
|-<br />
| Lunatic, manic, and radical Fringe<br />
| Fringe<br />
|<br />
| Modifies both Notch and its ligands<br />
|-bgcolor="F5FFFA" <br />
| ADAM10, ADAM17<br />
| Kuzbanian, Kuzbanian-like, TACE<br />
| SUP-17, ADM-4<br />
| Metalloproteases targeting S2 Notch cleavage sites<br />
|-<br />
| Presenilin 1-2, nicastrin, APH1, PEN2<br />
| Presenilin, nicastrin, APH1, PEN2<br />
| SEL-12, APH-1, APH-2, PEN2<br />
| Proteins of the γ-secretase complex, which targets Notch S3 and S4 cleavage sites<br />
|-bgcolor="F5FFFA" <br />
| Mind bomb, skeletrophin, neuralized 1-2<br />
| Mind bomb 1-2, neuralized<br />
| Y47D3A.22<br />
| E3 ubiquitin-protein ligases that targets Delta and Jagged/Serrate and regulate their endocytosis<br />
|}<br />
<br><br />
<br />
===Abnormalities in Notch Signalling===<br />
Mutations in Notch genes and hence defects in Notch signalling have been implicated in the pathogenesis of several inherited diseases in humans.<ref name="PMID23729744">As reviewed by <pubmed>23729744</pubmed></ref><ref name="PMID22306179">As reviewed by <pubmed>22306179</pubmed></ref> The diseases listed in this summary table are only a few examples and are described in more detail below.<br />
<br><br />
<br />
{| class="pretty table"<br />
|-bgcolor="CEDFF2" <br />
| '''Disease'''<br />
| '''Gene'''<br />
| '''Phenotype'''<br />
|-bgcolor="F5FAFF" <br />
| Alagille syndrome ([http://omim.org/entry/118450 OMIM118450], [http://omim.org/entry/610205 OMIM610205])<br />
| ''JAG1'', ''NOTCH2''<br />
| Developmental abnormalities of the heart, liver, eye, and skeleton. Neonatal jaundice and cholestasis are early symptoms.<br />
|-<br />
| CADASIL ([http://omim.org/entry/125310 OMIM125310])<br />
| ''NOTCH3''<br />
| Autosomal vascular disorders linked to ischemic strokes, dementia, and premature death.<br />
|-bgcolor="F5FAFF"<br />
| T-cell acute lymphoblastic leukaemia ([http://omim.org/entry/613065 OMIM613065])<br />
| ''NOTCH1'' (mutation in heterodimerization domain or PEST domain)<br />
| Tumour derived from T-cell progenitors. Symptoms include anaemia and enlargement of lymph nodes in the liver and/or spleen.<br />
|-<br />
| Spondylocostal dysostosis ([http://omim.org/entry/122600 OMIM122600])<br />
| ''DLL3'', Lunatic fringe<br />
| Vertebral segmentation defects as well as rib abnormalities.<br />
|}<br />
<br />
====Alagille Syndrome====<br />
Alagille syndrome (AGS) is an autosomal dominant, multisystem disorder that mainly affects the liver, heart, and kidney. Diagnostic characteristics of the disease include liver disease, cardiac disease, vertebral defects, eye conditions, and facial features, as well as renal and vascular abnormalities.<ref>As reviewed by <pubmed>26548814</pubmed></ref> Two variants of AGS, type 1 and type 2, have been identified, and each is related to different defects in the Notch pathway. In clinically diagnosed cases of AGS type 1 (which accounts for approximately 97% of all cases of AGS), a mutation in the gene encoding the Notch ligand Jagged1 (Jag1) has been identified as a contributing factor.<ref>As reviewed by <pubmed>11745040</pubmed></ref> In the much rarer AGS type 2, a mutation in the NOTCH2 gene has been implicated in the manifestation of AGS. The mechanisms by which mutations in JAG1 and NOTCH2 lead to pathogenesis of AGS are not well understood, but it is known that normal Notch signalling is important in angiogenesis. Therefore, it is thought that abnormal JAG1 or NOTCH2 will cause disruptions to the pathway that leads to the vascular disorders present in AGS. This is also evidenced by research that JAG1 knockout mice suffer premature death due to vascular defects.<ref>As reviewed by <pubmed>21934706</pubmed></ref> It is possible that AGS caused by a mutation in NOTCH2 alone will lead to a different presentation than AGS patients with mutated JAG1; however, this is still undergoing further research. It is also unclear why AGS type 2 occurs at a significantly lower incidence than AGS type 1.<ref><pubmed>16773578</pubmed></ref><br />
<br><br><br />
<br />
====Spondylocostal Dysostosis====<br />
Spondylocostal Dysostosis (SD) is a collective term for conditions characterised by anomalies relating to rib and spine. The vertebrae are fused and shaped abnormally which can result in scoliosis. Similarly, the ribs may also be fused together or in some cases completely missing. As a result, people with this condition have short trunk dwarfism where their bodies are short in stature but have normal length limbs. Genetic changes are known to cause SD. SD Type 1 is the most prevalent form of this disease which is caused by the mutation in the delta like canonical Notch ligand 3 (DLL3 gene).<ref><pubmed>10742114</pubmed></ref> DLL3 provides the information for making a protein that regulates the Notch signalling pathway. The DLL3 protein in conjunction with the Notch pathway is primarily responsible for preventing the fusion of future vertebrae in a process known as somite segmentation.<ref><pubmed>11236715</pubmed></ref> An interruption in the Notch pathway inhibits the somite segmentation resulting in abnormalities relating to the ribs and spine as seen in SD. 25 percent of SD arise from mutations in the identified genes and further research suggest that other genes involved in the Notch signalling pathway may also be related to SD.<br />
<br><br><br />
<br />
====Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)====<br />
CADASIL is an autosomal-dominant disease of the small to medium-sized arteries, mainly in the brain, that leads to dementia and disability in mid-life. The symptoms, age of onset, and prognosis are variable. Distinguishing symptoms include subcortical ischemic events (60-80% of cases), cognitive impairment (60% of late stage disease), migraines (30-40%), mood disturbances (30%), and apathy (40%).<ref name="PMID21045164"><pubmed>21045164</pubmed></ref><ref name="PMID20301673"><pubmed>20301673</pubmed></ref> Approximately 5-10% of CADASIL patients also experience seizures. The mean age of onset is 45 years of age and the disease duration is between 10–40 years. More than 95% of CADASIL cases present with pathogenic mutations in NOTCH3 (located on chromosome 19p13), specifically the epidermal growth factor-like repeat domain.<ref name="PMID20301673"/><ref><pubmed>24579972</pubmed></ref> The NOTCH3 gene is involved in the normal development of blood vessels in both fetal and adult brains. In adults, NOTCH3 is expressed in the smooth muscle cells of arteries.<ref name="PMID21045164"/> There is currently no effective treatment available for CADASIL.<br />
<br><br><br />
<br />
====Congenital Heart Defects====<br />
<br />
'''Aortic Valve Disease'''<br />
<br />
[[File:Aortic valve disease.jpg|thumb|450px|right|alt=Loss of NOTCH1 expression in proximity to calcific nodules in human aortic valves|'''Loss of NOTCH1 expression in proximity to calcific nodules in human aortic valves.''' (A) Representative sections from control (A,B) and diseased (C-F) aortic valve cusps. (B) is high magnification image of boxed area in (A) and (D,E) are higher magnification of region in (C) while image in (F) shows another calcified aortic valve. Expression of Notch1 intracellular domain (NICD) is found in the thickened fibrosa of diseased aortic valve (C,E) as compared to the acellular fibrosa of control valves (A,B). However, there is significant loss of NICD expression in cells residing adjacent to calcific nodules (D,F). The fibrosa is oriented upward in all panels, and scale bars equal 100 microns (B,D,E,F are at same magnification). Brown signal represents NICD expression while nuclei are counterstained in blue.<ref name="PMID22110751"><pubmed>22110751</pubmed></ref>]]<br />
<br />
Calcification of the aortic valve is a leading cause of adult heart disease. Mutations in NOTCH1 have been found to cause various aortic valve abnormalities, including the development of a bicuspid aortic valve (as opposed to tricuspid) and valve calcification.<br />
<br />
&emsp;&emsp;A study by Garg et al. (2005) looked at mouse embryos and the expression of ''Notch1'' during development. It was found that during normal embryonic development, ''Notch1'' was abundantly expressed in the outflow tract mesenchyme (which develops into the heart valves) and the endocardium, as well as in the endothelial layer and mesenchyme of the aortic valve leaflets at the time of arterial trunk septation. Abnormal ''Notch1'' led to the death of mice from vascular endothelial defects. Garg et al. then investigated whether NOTCH1 was involved in calcium deposition and therefore valve calcification. This is thought to be due to differentiation of valve cells into osteoblast-like cells. This leads to the upregulation of osteopontin, osteocalcin, and other osteoblast-specific genes, which is normally regulated by the transcription factor Runx2. Runx2 is known to be upregulated in animal models of valve calcification. Garg et al. found that Notch1 was capable of repressing Runx2 activation. Heart tissue and vasculature are normally abundant with the hairy-related transcriptional repressors Hrt1 and Hrt2 (also called Hey1 and Hey2), which are normally activated by Notch and are key mediators of the Notch pathway. Hrt1 and Hrt2 were both expressed in the endothelium of the mice aortic valve leaflets, the endocardium, and the vascular endothelium. They were found to inhibit the activation of osteoblast-specific genes by Runx2. It was thought that Hrt proteins can repress Runx2 by physical interaction as well as mediate Notch1 repression of Runx2. Therefore, a defect in Notch will cause upregulation of Runx2, due to the lack of repressor activity by Notch itself and the activation of the repressors Hrt1 and Hrt2. This leads to the expression of osteoblast genes that results in the differentiation of valvular cells into osteoblast-like cells and ultimately causes aortic valve calficiation.<ref><pubmed>16025100</pubmed></ref><br />
<br />
The picture to the right is a histological image of aortic valve disease from a study performed in rats investigating molecular changes that occurred when Notch signalling was suppressed in the aortic valve.<ref name="PMID22110751"/><br />
<br><br><br />
<br />
====Tumourigenesis====<br />
Notch has been shown to be involved in cancer development and can act as both an oncogene and a tumour suppressor gene.<ref>As reviewed by <pubmed>14570040</pubmed></ref><ref name="PMID23729744"/> Defective Notch signalling has been implicated in the pathogenesis of several human cancers, such as acute myelogenous leukemia (overexpression of Jagged1 and Notch1), multiple myeloma (overexpression of Jagged1/2 and Notch1/2), and B-cell–derived Hodgkin lymphoma (overexpression of Jagged1 and Notch1).<ref name="PMID16291593">As reviewed by <pubmed>16291593</pubmed></ref><br />
<br />
Elevated levels of Notch ligand proteins and/or mRNA have been observed in several cancers. Upregulated Jagged1 mRNA has been seen in human pancreatic cancer; Jagged1 protein overexpression has also been studied in prostate, cervix, and brain cancers. Cervical cancers have shown upregulated Jagged2 mRNA. Additionally, elevated Dll1 mRNA has been observed in cervical cancers, as well as in human brain cancers at both Dll1 mRNA and protein levels. Additionally, defective Notch receptor expression has been implicated in cancer as well. For example, elevated Notch1 protein expression has been found in cervical, colon, lung, pancreas, skin, and brain cancers. Protein overexpression of Notch3 and Notch4 has also been seen in malignant melanoma and pancreatic cancer.<ref name="PMID16291593"/><br />
<br />
Interestingly, research has shown that Notch signalling can also have a tumour-suppressive effect. Studies have indicated that Notch signalling can inhibit proliferation and even stimulate apoptosis in malignant B-cells. Furthermore, the Notch1 intracellular domain has also shown the ability to induce growth arrest and apoptosis in Hodgkin lymphoma and multiple myeloma cells.<ref name="PMID16291593"/><br />
<br><br><br />
<br />
'''T-Cell Acute Lymphoblastic Leukaemia'''<br><br />
T-cell acute lymphoblastic leukaemia (T-ALL) is an example of how abnormal Notch signalling can lead to the development of cancer. T-ALL is an aggressive childhood cancer of the immune system's T-cells. The NOTCH1 gene encodes the Notch1 receptor, which is involved in the determination of pluripotent cell progenitors to T-cells and the organisation of these cells in the developing thymus. Activating mutations in the extracellular domain and/or the C-terminal PEST domain of Notch1 have been identified in more than half of all cases of T-ALL.<ref><pubmed>15472075</pubmed></ref><br />
<br><br><br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Other Examples of Roles of Notch in Cancer <small>(adapted from ''Notch in disease''<ref name="PMID23729744"/>)</small><br />
|-<br />
|-bgcolor="a3bfb1"<br />
| '''Gene'''<br />
| '''Role of Notch'''<br />
| '''Disease'''<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br>''NOTCH2''<br />
| Oncogene<br>Tumour suppressor<br />
| Pancreatic ductal adenocarcinoma<br />
|-<br />
| ''NCSTN''<br>''MAML1''<br>''APH1A''<br>''NOTCH2''<br />
| Tumour suppressor<br />
| Chronic myelomonocytic leukaemia<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br />
| Oncogene<br />
| Chronic lymphocytic leukaemia<br />
|-<br />
| Activated NOTCH<br />
| Tumour suppressor<br />
| Hepatocellular carcinoma<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br>''NOTCH2''<br>''NOTCH3''<br />
| Tumour suppressor<br />
| Head and neck squamous cell carcinoma<br />
|-<br />
| NOTCH<br />
| Tumour suppressor<br />
| B-cell acute lymphoblastic leukaemia<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br />
| Oncogene<br />
| Non-small-cell lung cancer<br />
|-<br />
| ''NOTCH1''<br />
| Oncogene<br />
| T-cell acute lymphoblastic leukaemia<br />
|}<br />
<br><br />
<br />
====Quiz Your Notch-Knowledge on Abnormalities in Notch Signalling!====<br />
<br />
<quiz display=simple><br />
{ What is the name for the collection of rib and spine abnormalities that result from interruption in the Notch pathway that leads to inhibition of somite segmentation in the embryo?<br />
|type="()"}<br />
- &nbsp; Alagille Syndrome<br />
- &nbsp; T-cell acute lymphoblastic leukaemia<br />
+ &nbsp; Spondylocostal Dysostosis<br />
- &nbsp; CADASIL<br />
|| Remember, Spondylocostal Dysostosis is a collective term for conditions characterised by anomalies relating to rib and spine. Genetic changes lead to an interruption in the Notch pathway that inhibits the somite segmentation resulting in abnormalities relating to the ribs and spine. Alagille syndrome is an autosomal dominant, multisystem disorder that mainly affects the liver, heart, and kidney. T-cell acute lymphoblastic leukaemia is an aggressive childhood cancer of the immune system's T-cells. CADASIL is an autosomal-dominant disease of the small to medium-sized arteries, mainly in the brain, that leads to dementia and disability in mid-life.<br />
</quiz><br />
<br />
===Current Areas of Research and Future Directions===<br />
Notch has been identified as having a role in the development of several cancers, and therefore research has recently begun investigating the use of Notch inhibitors in cancer treatment.<ref>As reviewed by <pubmed>27732970</pubmed></ref> γ-secretase inhibitors (GSIs), which inhibit the normal cleavage of Notch at the cell membrane and hence NICD release, have been a popular area of research. In the specific case of desmoid tumours, it was observed that treatment GSIs resulted in decreases in NICD and Hes1 expression in the tumour cells. Overall, tumour cell migration and invasion were decreased and cell growth was also inhibited.<ref><pubmed>26349011</pubmed></ref> GSIs have also been shown to have an inhibitory growth effect on pancreatic, breast, and lung cancers, but unfortunately they also produce side effects ''in vivo''.<ref>As reviewed by <pubmed>27688721</pubmed></ref> Therefore continued study into GSIs is required to make them safe for human treatment. Ultimately, with ongoing research, it is possible that the Notch pathway will eventually become an effective therapeutic target for cancers.<br />
<br><br><br />
<br />
<big><b>To search and read recent PubMed research and review articles on Notch, click <u>[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=Notch here]</u>!</b></big><br />
<br><br><br />
<br />
===Want to Read More About Notch?===<br />
The [http://www.omim.org/ OMIM (Online Mendelian Inheritance in Man) database] contains extensive information about the Notch genes and associated proteins and is a great place to go if you want to find out more about the Notch pathway in humans! Click on these links to learn more about the Notch genes that encode the human receptors and ligands:<br />
<li>[http://www.omim.org/entry/190198 NOTCH1] | [http://www.omim.org/entry/600275 NOTCH2] | [http://www.omim.org/entry/600276 NOTCH3] | [http://www.omim.org/entry/164951 NOTCH4]<br />
<li>[http://www.omim.org/entry/601920 JAG1] | [http://www.omim.org/entry/602570 JAG2]<br />
<li>[http://www.omim.org/entry/606582 DLL1] | [http://www.omim.org/entry/602768 DLL3] | [http://www.omim.org/entry/605185 DLL4]<br />
<br><br><br />
<br />
You can also look at these papers for examples of reviews and research papers that reinforce the diversity of how the Notch pathway functions in organisms.<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch influences adult development as well!</big><br />
|-<br />
|Interestingly, Notch does not only play a role in human embryonic development, but has also been found to influence developmental processes after birth. One of these processes is neurogenesis, for example.<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159580/ '''Not(ch) just development: Notch signalling in the adult brain.'''] <br />
<br />
This review explains that the Notch signalling pathway, which is so often regarded as a major molecular player in development, actually has important functions related to neural cells in the adult. As you would have read in the [[#Abnormalities in Notch signalling| Abnormalities in Notch Signalling]] section, Notch abnormalities are involved in a number of diseases, which underlines its importance in maintaining adult brain function. Some highlights of this review are: Figure 2 provides a schematic representation of precise roles Notch activation can play in the adult brain; explanations of the ways that Notch influences brain plasticity; and the discussion of conflicting results of studies exploring the role of Notch in stroke recovery.<ref name=PMID21505516><pubmed>21505516</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch Modulation for Therapy</big><br />
|-<br />
|As you would have read in the [[#Abnormalities in Notch signalling| Abnormalities in Notch Signalling]] section, Notch can play different roles in cancer development. An interesting review further elucidates that modulation of Notch signalling is actually being investigated as a potential target for cancer therapy:<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704338/ '''Targeting the Notch signaling pathway in cancer therapeutics'''] <br />
<br />
This articles focuses on reviewing data emerging from recent research, explaining how Notch contributes to the development of a number of cancers, and then outlining the current focuses of investigations into how to therapeutically manipulate the Notch pathway. Some highlights from this review are: the detailed description of how Notch interacts with other signalling pathways such as Wnt and the signalling cytokine Interleukin-6; explanations of the seemingly conflicting roles of Notch as a tumour promoter and suppressor; and discussion of the findings of various Notch-related studies in cancer stem cells.<ref name=PMID26767041><pubmed>26767041</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch influences reproduction in worker honey bees!</big><br />
|-<br />
| In our [[#Roles in Animal Development| Roles in Animal Development]] section we discussed Notch in relation to a number of animals, however one that we did not cover was the worker honey bee, or ''Apis mellifera''. A recent study shows that Notch also plays a role in these honeybees!<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976197/ '''Notch signalling mediates reproductive constraint in the adult worker honeybee.'''] <br />
<br />
This research paper essentially concludes that in the worker honeybee Notch signalling constrains reproduction between males and females; they were the first team to elucidate a molecular mechanism underlying the link between adult ovary activity in bees and the presence of the queen bee. Some highlights from this unique and interesting study are: the background explanation that female worker bees have suppressed activity due to pheromones produced by the queen; the finding that Notch plays a part in this inactivation of reproductivity; and the discussion about social control of reproduction and evolution.<ref name=PMID27485026><pubmed>27485026</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch signalling is involved in embryo implantation!</big><br />
|-<br />
| Notch is essential for many developmental embryonic processes, as described in our [[#Roles in Embryonic Development|Roles in Embryonic Development]] section. Interestingly, research has shown that Notch signalling also has an important role in the initial process of establishing a successful pregnancy. Specifically, normal Notch signalling has been seen to be a critical factor in fetal-maternal communication during implantation and placentation. (To read more about these processes, go to these pages on [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Week_1_and_2_Development Weeks 1-2] and [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Week_3_Development Week 3] of development.)<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/24357662 '''Fetal-maternal communication: the role of Notch signalling in embryo implantation.''']<ref>As reviewed by <pubmed>24357662</pubmed></ref><br />
<br />
This review describes both human and animal studies of Notch signalling during pregnancy. It explains research of Notch signalling at the human blastocyst-maternal interface, and that Notch signalling has been observed in both the maternal endometrium and the blastocyst. Furthermore, Notch signalling is also important for the processes of implantation and placentation. Overall, the review summarises findings of Notch signalling in endometrial-trophectoderm interactions during the implantation, regulation of extravillous trophoblast invasion and spiral artery remodelling in the decidua, and angiogenesis in the placenta, as well as how abnormal Notch signalling is related with impaired placentation and pre-eclampsia.<br />
|}<br />
<br><br />
<br />
===Glossary===<br />
{| class="pretty table"<br />
|-<br />
| '''AER'''<br />
| 'Apical Ectodermal Ridge' is a structure that forms from the ectodermal cells at the distal end of each limb bud. The AER acts as a major signalling centre in order to ensure proper limb development.<br />
|-<br />
| '''Apoptosis'''<br />
| Programmed cell death which occurs in the development of many systems.<br />
|-<br />
| '''Calcification'''<br />
| The accumulation of calcium salts in body tissue. It normally occurs in the formation of bone, but abnormally calcium can be deposited in soft tissue causing it to harden.<br />
|-<br />
| '''Cardiogenic'''<br />
| From cardiogenesis - meaning formation of the heart.<br />
|-<br />
| '''Cardiomyocyte'''<br />
| The muscle cells (myocytes) that make up the cardiac muscle<br />
|-<br />
| '''Congenital'''<br />
| (Of a disease or physical abnormality) present from birth.<br />
|-<br />
| '''Craniofacial'''<br />
| Meaning relating to the cranium and the face.<br />
|-<br />
| '''Cyclin D1'''<br />
| A protein required for progression through the G1 phase of the cell cycle. Read more about it [https://en.wikipedia.org/wiki/Cyclin_D1 here], or see information on its encoding gene here: [http://omim.org/entry/168461 OMIM168461].<br />
|-<br />
| '''Endocardial'''<br />
| From endocardium - meaning the thin, smooth membrane which lines the inside of the chambers of the heart and forms the surface of the valves.<br />
|-<br />
| '''Endocrine'''<br />
| As in the endocrine system, refers to glands that secrete hormones or other substances directly into the blood.<br />
|-<br />
| '''Epithelium'''<br />
| The thin tissue that forms the outer layer of a body's surface and also lines the alimentary canal and other hollow structures.<br />
|-<br />
| '''Gastrulation'''<br />
| Describes the formative process of the formation of the trilaminar embryo containing the three germ layers.<br />
|-<br />
| '''Gliogenesis'''<br />
| The formation and development of glial cells (astrocytes, oligodendrocytes, Schwann cells, microglia).<br />
|-<br />
| '''Haematopoietic'''<br />
| From haematopoiesis - meaning the formation of blood cellular components<br />
|-<br />
| '''Haploinsufficiency'''<br />
| When a diploid organism has only a single functional copy of a gene (with the other copy inactivated by mutation), and so the total level of a gene product (a particular protein) produced by the cell is about half of the normal level.<br />
|-<br />
| '''Homeostasis'''<br />
| The ability to maintain a constant internal environment in response to environmental changes.<br />
|-<br />
| '''Ligand'''<br />
| A molecule that binds to a specific binding site on a protein (receptor).<br />
|-<br />
| '''Mef2C promoters'''<br />
| Myocyte-specific enhancer factor 2C is a transcription factor in the Mef2 family that is encoded by the gene ''MEF2C'' in humans ([https://omim.org/entry/600662 OMIM 600662]). This gene is involved in cardiac morphogenesis and myogenesis, as well as vascular development. It is thought to also possibly play a role in neurogenesis.<br />
|-<br />
| '''Mesenchymal'''<br />
| From mesenchyme - meaning a loosely organised, mainly mesodermal embryonic tissue which develops into connective and skeletal tissues, including blood and lymph.<br />
|-<br />
| '''Morphogenesis'''<br />
| Refers to the origin and development of morphological characteristics.<br />
|-<br />
| '''Myogenic'''<br />
| From myogenesis - meaning formation of muscle.<br />
|-<br />
| '''Myogenin'''<br />
| Also known as myogenic factor 4, this is a muscle-specific basic-helix-loop-helix transcription factor involved in the coordination of skeletal muscle development or myogenesis and repair.<br />
|-<br />
| '''Neural Crest'''<br />
| In vertebrate embryos, this is a transient structure that gives rise to most of the peripheral nervous system and to a number of non-neural cell types such as the smooth muscle cells of the cardiovascular system. <br />
|-<br />
| '''Neurogenic'''<br />
| From neurogenesis - meaning the formation of nervous tissue.<br />
|-<br />
| '''Neurulation'''<br />
| The folding process in vertebrate embryos whereby the neural plate transforms into the neural tube.<br />
|-<br />
| '''NICD'''<br />
| Notch intracellular domain<br />
|-<br />
| '''Oncogenic'''<br />
| From oncogenesis, also known as tumorigenesis or carcinogenesis - meaning the formation of a cancer, whereby normal cells are transformed into cancer cells.<br />
|-<br />
| '''Paracrine'''<br />
| A hormone that exerts an effect only in the vicinity of the gland secreting it.<br />
|-<br />
| '''Protease'''<br />
| An enzyme which breaks down proteins and peptides.<br />
|-<br />
| '''Runx2'''<br />
| Runt-related transcription factor 2 is a protein that in humans is encoded by the ''RUNX2'' gene ([http://omim.org/entry/600211 OMIM600211]). RUNX2 is an important transcription factor associated with osteoblast (bone substance-secreting cells) differentiation.<br />
|-<br />
| '''Stromal cells'''<br />
| The connective tissue cells of any organ. They support the function of the parenchymal cells of that organ. Fibroblasts and pericytes are among the most common types of stromal cells.<br />
|-<br />
|}<br />
<br />
====Further Glossary Links====<br />
[[A|A]] | [[B|B]] | [[C|C]] | [[D|D]] | [[E|E]] | [[F|F]] | [[G|G]] | [[H|H]] | [[I|I]] | [[J|J]] | [[K|K]] | [[L|L]] | [[M|M]] | [[N|N]] | [[O|O]] | [[P|P]] | [[Q|Q]] | [[R|R]] | [[S|S]] | [[T|T]] | [[U|U]] | [[V|V]] | [[W|W]] | [[X|X]] | [[Y|Y]] | [[Z|Z]] | [[Numbers|#]]<br />
<br />
===References===<br />
<references/></div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=2016_Group_Project_2&diff=255166
2016 Group Project 2
2016-10-27T07:59:40Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016header}}<br />
{{Group Assessment Criteria table}}<br />
<!-- Do not delete the above template from the Group project page. --><br />
=The Notch Signalling Pathway=<br />
===Introduction===<br />
The Notch signalling pathway is the most prevalent form of intracellular communication in multicellular organisms. It is a critical pathway for cell differentiation, proliferation, and apoptosis. It is involved in embryonic organ development through the regulation of cell-cell signalling; specifically lateral inhibition, formation of boundaries, and cell lineage assignation.<ref name="The Developing Human">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2015). The developing human: clinically oriented embryology (10th ed.). Philadelphia: Saunders.</ref><ref name="PMID10075488">As reviewed by <pubmed>10075488</pubmed></ref> This pathway is also actively involved in adjacent cell communication, developmental process such as adult homeostasis, and stem cell maintenance. Since this pathway is an intricate and crucial aspect of an organism's development and cell signalling, a mutation in the functional components of this pathway can cause a myriad of diseases such as congenital disorders, cancers, strokes, Alagille syndrome, and leukoencephalopathy.<ref name="PMID19255248">As reviewed by <pubmed>19255248</pubmed></ref> The process of Notch signalling primarily utilises a ligand-receptor interaction to release protein fragments at the cellular membrane, which then provide signals to the internal environment of the cell and to adjacent cells. In mammals, the Notch signalling pathway is comprised of four receptors (Notch 1-4) which interact with Delta or Jagged ligands to bring about the activation of this pathway. Homologous Notch genes have been identified in other animals, such as ''Drosophila melanogaster'' (fruit fly) and ''Danio rerio'' (zebrafish).<br />
<br><br />
<br />
<big>What will you find on this wiki page?</big><br />
<br />
This page is designed to provide an overview of such features of the Notch signalling pathway, but is in no way a complete resource for all Notch-related information (especially since this signalling pathway has such a wide array of activities in many organisms and the scientific understanding of it is continuously updating!). By reading this page you should come to a better understanding of Notch in regards to: general molecular mechanisms; embryonic development by systems; examples of animal development; abnormalities and disease; current and potential future research; as well as a couple of links to interesting articles for those who want to read more. There is a [[#Glossary| Glossary]] at the bottom of the page for better understanding of scientific terms used throughout this page, and readers are encouraged to 'expand' any collapsed information on the page to optimise their experience in reading about Notch. <br />
<br><br><br />
<div align="center"><html5media width="560" height="315">https://www.youtube.com/embed/axkDX0XZyN0</html5media></div><br />
<br><br />
<br />
===History===<br />
{| class="pretty table"<br />
|-bgcolor="FAF5FF" <br />
| 1914<br />
| First description of a "notch" defect (loss of tissue in the wing) in ''Drosophila'' by John S. Dexter, giving the gene its name<ref>Dexter, J. (1914). The Analysis of a Case of Continuous Variation in Drosophila by a Study of Its Linkage Relations. ''The American Naturalist'', 48(576), 712-758. Retrieved from http://www.jstor.org/stable/2455888</ref><br />
|-<br />
| 1917<br />
| First allele of ''Notch'' is identified by Thomas Hunt Morgan<ref>Morgan, T. H. (1917). The theory of the gene. ''The American Naturalist'', 51(609), 513-544.</ref><br />
|-bgcolor="FAF5FF" <br />
|-<br />
| 1930s<br />
| Donald F. Poulson conducts research into the involvement of ''Notch'' in development.<ref><pubmed>16588136</pubmed></ref> <br />
|-<br />
| 1958<br />
| An investigation by W.J. Welshons confirmed that the locus of Notch is contained within the 3C7 band of the X chromosome.<ref><pubmed>13635554</pubmed></ref><br />
|-bgcolor="FAF5FF" <br />
| 1983<br />
| DNA sequences belonging to the Notch locus cloned and determined that RNA is required for the function of the wild type Notch. Further insight developed into the function of Notch and its role in differentiation and regeneration.<ref><pubmed>6403942</pubmed></ref><br />
|-<br />
| 1986<br />
| The molecular analysis and sequence of the Notch locus was determined by Michael W. Young and his team. A relationship was identified between the protein encoded by the major Notch transcript and mammalian clotting and growth factors.<ref><pubmed>3097517</pubmed></ref><br />
|-bgcolor="FAF5FF" <br />
| 1989<br />
| Neurogenic loci "Delta" and "Mastermind" identified and research conducted to search for genes which may have an interaction with the Notch protein. It was confirmed that mutations in these loci will affect neurogenesis.<br />
|}<br />
<br />
===Overview of Molecular Mechanisms===<br />
Mammals possess a total of four ''Notch'' genes, with five genes for encoding the associated ligands, Delta-like and Jagged. The ''Notch'' genes each code for a single transmembrane receptor. Extracellularly, it contains epidermal growth factor (EGF)-like repeats for ligand interaction and Lin-12-Notch (LN) repeats for regulating the interactions between the extracellular and intracellular regions. Intracellularly, Notch has seven ankyrin (ANK) repeats and a transactivation domain (TAD), as well as a proline, glutamine, serine, threonine-rich (PEST) domain for degradation of Notch.<br />
<br><br><br />
[[File:Notch structure cartoon.jpg|thumb|700px|center|'''The structure of the Notch receptor.'''<ref name="PMID19255248"/> Extracellularly there are epidermal growth factor (EGF)-like repeats and Lin-12-Notch repeats (LNRs). The Notch intracellular domain (NICD) is made up of a rRBP-Jkappa-associated module (RAM) domain, ankyrin (ANK) repeats, and a proline, glutamine, serine, threonine-rich (PEST) domain. There are three sites for cleavage by enzymes: S1, S2, and S3/S4.]]<br />
<br />
====Canonical pathway====<br />
[[File:Overview of Notch signalling.png|thumb|500px|'''Summary of canonical Notch signalling.''' The interaction between Delta-like or Serrate ligands (DSL) and the Notch receptor on an adjacent cell initiates proteolytic cleavage of Notch and the release of the Notch intracellular domain (NICD). The NICD is then transported to the nucleus where it can induce transcription of Notch target genes by binding to specific proteins (MAM, CSL).<ref><pubmed>27404588</pubmed></ref>]]<br />
The canonical Notch pathway is unique in that it involves direct interaction between adjacent cells, as opposed to paracrine signalling, because both the Notch ligands and Notch receptors are transmembrane proteins found in the cell membrane. Furthermore, the lack of a secondary messenger or amplification process means that the Notch pathway has limited opportunities for regulation and must therefore be tightly controlled. Depending on its developmental and cellular context, activation or inhibition of the pathway can result in a variety of cellular responses, including cell death, proliferation, or differentiation.<ref name="Introduction to Notch Signalling">Yamamoto, S., Schulze, K.L. & Bellen, H.J. (2014). Introduction to Notch Signalling. ''Notch Signaling: Methods and Protocols''. Methods in Molecular Biology: 1187</ref><br />
<br><br><br />
Four Notch proteins are involved in the canonical pathway. NOTCH1 to NOTCH4 are single transmembrane receptors and can interact with a variety of ligands, including NOTCH ligands (e.g. Delta ligands) and Serrate ligands. There are three Delta ligands (Dll1, Dll3, and Dll4) and two Serrate ligands (Jagged1 and Jagged2) present in mammals.<ref name="Introduction to Notch Signalling"/> The binding between the Notch receptor and the ligand on the adjacent cell induces the release of the Notch intracellular domain (NICD) via a sequence of proteolytic reactions.<ref name="The Developing Human"/> Cell-cell interaction is therefore critical in the process of triggering Notch signalling.<br />
<br><br><br />
The interaction on the cell surface between Notch and its ligand on an adjacent cell causes the extracellular metalloprotease site (S2 site) to be exposed. The S2 site is then cleaved by transmembrane proteases belonging to the a disintegrin and metalloproteinase/tumour necrosis factor α converting enzyme (ADAM/TACE) family. The remaining Notch fragment subsequently undergoes two more intramembranous cleavages at the S3/S4 sites by the γ-secretase complex. Finally, the NICD is released and enters the nucleus to interact with CSL (CBF1, Suppressor of Hairless, Lag-1) and Mastermind-like proteins (MAMLs). CSL is a DNA-binding protein that acts as a transcription factor by forming repressor or activator complexes; in the absence of the NCID, CSL is bound to corepressor proteins (CoR) that prevent transcription of Notch target genes. MAMLs are transcriptional co-activators that are required for transcription of the target genes, hence they are involved in the regulation of the pathway.<ref name=PMID10075488/><ref name="Introduction to Notch Signalling"/> To stop signalling, the NICD is phosphorylated by kinases and ubiquitinated by E3 ubiquitin ligases, which results in proteasome mediated degradation and subsequent termination of the signal.<ref name="Introduction to Notch Signalling"/><br />
<br><br><br />
<br />
====Non-canonical pathway====<br />
Immense research has been carried out on the canonical Notch pathway and its members are well known. While canonical notch ligands control most of the known Notch signalling, a group of structurally distinct non-canonical ligands exist which activate Notch and its pleiotropic effects. Notch can non-canonically carry out its functions by post-translationally targeting Wnt/β-catenin signalling. This type of signalling is CSL-independent and can also work independently of ligands. Some genes are affected by the non-canonical Notch signalling, however their mediators in most cases are unknown. Notch binds and titrates levels of active β-catenin. Therefore, active β-catenin activity may serve as a useful readout for non-canonical Notch signals.<ref name="PMID22397947">As reviewed by <pubmed>22397947</pubmed></ref> <br />
<br />
Recent research has shown that Notch signalling plays crucial roles for cellular differentiation during development through γ-secretase-dependent intramembrane proteolysis followed by transcription of target genes. Hayashi et al. (2016) uncovered a ligand-dependent but γ-secretase-independent, non-canonical Notch signalling involved in presynaptic protein expression in postmitotic neurons.<ref name="PMID27040987"><pubmed>27040987</pubmed></ref><br />
<br><br><br />
<br />
====Transcriptional regulation of Notch signalling====<br />
A number of genes have been found to act as modulators of Notch signalling by modifying the ability of Notch to interact with its ligands. These include proteins acting extracellularly (Fringe, Brainiac, Egghead, Scabrous, Wingless), proteins acting at the cell membrane (Big brain), proteins acting intracellularly (Numb, Sanpodo, Disabled, Deltex, Dishevelled), and proteins acting within the nucleus (Hairless, EMB-5, Strawberry notch).<ref name="PMID9892565">As reviewed by <pubmed>9892565</pubmed></ref><br />
<br />
In ''Drosophila melanogaster'', it has been seen that ''fringe'' is able to affect the ability of Notch to be activated by the Serrate and Delta ligands. Specifically in the ''Drosophila'' wing, it was observed that Serrate did not interact with Notch in specific areas due to the action of ''fringe''<ref><pubmed>9247339</pubmed></ref>. Fringe is not required for initial Notch signalling, but is thought to be important for signalling processes when Notch activation occurs along the borders between distinct cell populations. Research suggests that Fringe specifically affects the binding between Notch and its ligands, rather than an activation step separate or subsequent to ligand binding. The ''brainiac'' and ''egghead'' genes are thought to either influence the production of a Notch ligand or act as substitute ligands themselves.<ref name="PMID9892565"/><br />
<br><br><br />
<br />
====Examples of Proteins Involved in Interaction with the Notch Intracellular Domain <small>(adapted from Table 3<ref name="PMID21828089"/>)</small>====<br />
{| class="pretty table"<br />
|-bgcolor="A3BFB1" <br />
| '''Protein'''<br />
| '''Interaction with NICD'''<br />
|-bgcolor="F5FFFA"<br />
| Adenamatous polyposis coli (Apc)<br />
| Controls Notch trafficking<br />
|-<br />
| Cyclin-dependant kinase 8 (CDK8)<br />
| Phosphorylates NICD to make it a substrate for ubiquitylation and degradation<br />
|-bgcolor="F5FFFA"<br />
| CBF1, Su(H) and LAG-1/Recombination signal binding protein for immunoglobulin kappa J region (CSL/RBP-J)<br />
| Main canonical transcriptional co-factor for NICD<br />
|-<br />
| Cyclin C (CycC)<br />
| Targets NICD for phosphorylation to make it a substrate for ubiquitylation and degradation<br />
|-bgcolor="F5FFFA"<br />
| Dishevelled (Dsh/Dvl)<br />
| Controls ligand-independent Notch trafficking; inhibits canonical Notch signalling<br />
|-<br />
| Deltex-1-4 (Dtx1-4)<br />
| Controls Notch ubiquitylation, processing, and internalisation<br />
|-bgcolor="F5FFFA"<br />
| Itchy, E3 ubiquitin protein ligase (Itch)<br />
| Promotes ubiquitylation of NICD<br />
|-<br />
| Mastermind-like 1/2 (Maml1/2)<br />
| Co-activator for NICD/CSL<br />
|-bgcolor="F5FFFA"<br />
| Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-ϰb)<br />
| NICD blocks NF-ϰb transcription of NF-ϰb target genes through binding to p50/cRel<br>NICD enhances NF-ϰb transcription of target genes by retaining NF-ϰb in the nucleus<br />
|-<br />
| Numb homolog (Numb)<br />
| Suppresses Notch signaling by recruiting E3 ubiquitin ligases to ubiquitylate Notch<br>Controls Notch trafficking during asymmetric cell division<br />
|-bgcolor="F5FFFA"<br />
| Smad family members (SMAD)<br />
| Smads enhance Notch signalling; Notch fine-tunes signalling through Smads<br />
|}<br />
<br><br />
<br />
===Roles in Embryonic Development===<br />
The phylogenetically conserved Notch signalling pathway plays a crucial role in the development of multiple organ systems, and is a major regulator of stem cell fate. It is responsible for the regulation of the transcription of a number of signalling molecules, such as ''MyoD'', ''Mash1'' and ''GATA2'', which are genes controlling the fate of myogenic, neurogenic and haematopoietic stem cells, respectively. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> The following subsections will further elucidate the vital roles of Notch signalling during normal embryonic development. If you would like to better understand human embryonic development before reading this section, [https://embryology.med.unsw.edu.au/embryology/index.php/Embryonic_Development| this page] serves as a great resource. <br />
<br><br><br />
<br />
====Cardiovascular====<br />
<br />
If you would like to generally learn about and become familiar with cardiac development in the embryo before reading this section, click [https://embryology.med.unsw.edu.au/embryology/index.php/ANAT2341_Lab_11_-_Heart here]!<br />
<br />
'''Cardiomyocyte Specification and Differentiation'''<br />
<br />
Expression during the appropriate window of the timeline of embryogenesis of Notch receptors, ligands and downstream effector molecules elucidates a role for the Notch pathway in the earliest stages of cardiac development. It has been found to restrict the expression of specific cardiogenic genes in a spatiotemporal manner and regulate cardiac field specification as early as during gastrulation. <ref name=PMID19580804><pubmed>19580804</pubmed></ref> Interestingly, Notch has been found to play both suppressive and promoting roles in cardiogenesis.<br />
<br />
For example, it has been shown that Notch suppresses cardiomyocyte cell fate specification during early cardiogenesis. This has been demonstrated through studies such as that carried out by Rones and colleagues (2000), which used activation and inhibition of Notch signaling in Xenopus. <ref name=PMID10934030><pubmed>10934030</pubmed></ref><br />
<br />
On the other hand, studies such as that by Boni et al. (2008) have found that Notch signalling may also promote myogenesis from cardiac progenitor cells. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> Cardiogenesis has also been promoted by downregulating Notch-1 activity in stem cells of embryos (Nemir et al., 2006).<ref name=PMID16690879><pubmed>16690879</pubmed></ref><br />
<br />
Despite the understanding that Notch signalling is crucial to embryonic myogenesis, the exact molecular mechanism remains elusive. Research by Buas and colleagues (2010) has explored such mechanisms by studying the Notch target, Hey1, which is known to suppress myogenic differentiation. They concluded that this inhibitory function of Hey1 is primarily mediated through binding near to myogenin and Mef2C promoters, which leads to cessation of target gene expression. <ref name=PMID19917614><pubmed>19917614</pubmed></ref><br />
<br />
[[File:Notch CVS simple diagram.png|thumb|500px|right|alt=Simplified Scheme of the Roles of Notch in Cardiac Development|'''Simplified Scheme of the Roles of Notch in Cardiac Development.''' Notch has been found to restrict the expression of specific cardiogenic genes in a spatiotemporal manner and regulate cardiac field specification early in development. Further after cardiac differentiation, Notch influences development of the AVC (atrioventricular canal), cardiac valves, ventricular trabeculae and the cardiac outflow tract. (This student-drawn image is based upon Figure 2 in the 2014 review by Zhou and Liu: [https://www.ncbi.nlm.nih.gov/pubmed/24345875 ''Role of Notch signaling in the mammalian heart.'']<ref name=PMID24345875><pubmed>24345875</pubmed></ref>)]]<br />
<br />
'''Development of the Atrioventricular Canal'''<br />
<br />
A study by Rutenberg et al. (2006) and another by Kokubo et al. (2007) implicate a role for Notch signaling in the region between the atria and the ventricles of the heart (the atrioventricular canal, or AVC).<ref name=PMID17021042><pubmed>17021042</pubmed></ref> <ref name=PMID17259303><pubmed>17259303</pubmed></ref> They used chicken and mouse models, respectively, to show that other signalling factors, ''Bmp2'' and ''Tbx2'', are restricted to the AVC region by Notch signalling during development. <br />
<br />
Furthermore, Watanabe and colleagues (2006) showed that deletion of Notch targets increases ''Bmp2'' expression and expansion of the AVC tissue, however other, non-Notch restrictive factors involved in AVC development are likely to exist.<ref name=PMID16554359><pubmed>16554359</pubmed></ref> <br />
<br />
'''Heart Valve Development'''<br />
<br />
In order for the heart valve to properly form in the embryo, endocardial to mesenchymal transformation (EMT) must occur. The Notch pathway, alongside Wnt and Bmp, has been found to regulate the process of EMT, defects in which can lead to congenital heart valve disease. Interestingly, Timmerman and colleagues (2004) demonstrated that this role of Notch may also promote oncogenic transformation. This team also showed that embryos exhibited abortive endocardial EMT if they were deficient in Notch signalling components in vivo and in vitro. <ref name=PMID14701881><pubmed>14701881</pubmed></ref> <br />
<br />
A more recent paper by Wang et al. (2013) further explored the underlying signalling processes and interrelationships of molecules that impact EMT. They found that Jagged1-Notch1 signalling in cells of the endocardium potentiates expression of Wnt4, which in turn carries out paracrine action on adjacent AVC tissue to upregulate Bmp2 expression and thus signal EMT. <ref name=PMID23560082><pubmed>23560082</pubmed></ref><br />
<br />
'''Trabeculation'''<br />
<br />
Trabeculation is the initial process of ventricular chamber development that forms a series of cardiomyocyte projections within the lumens of the ventricles of the heart (called trabeculae). Grego-Bessa and colleagues (2007) addressed the roles Notch plays in trabeculation through ''RBPJk'' (the gene product of which interacts with Notch) and ''Notch1'' gene manipulation. Mutants of these two genes showed perturbed expression and signalling of ''EphrinB2'', ''NRG1'' and ''BMP10'', alongside reduced proliferation of myocardiocytes. This research ultimately suggested that ''EphrinB2'' is a direct target of Notch in the endocardium that simultaneously requires the Notch-dependent action of BMP10 and NRG1 in order for ventricular myocardium proliferation and differentiation to occur normally. <ref name=PMID17336907><pubmed>17336907</pubmed></ref> Furthermore, the important process of trabeculation has recently been shown to be controlled by sequential Notch activation by an investigation by D’Amato et al. (2015). <ref name=PMID26641715><pubmed>26641715</pubmed></ref><br />
<br />
'''Development of the Outflow Tract'''<br />
<br />
About one third of congenital heart defects include malformations in the outflow tract which include the aorta, pulmonary arteries, aortic arch and ductus arteriosus. During cardiogenesis, neural crest cells interact with second heart field myocardium and endocardial mesenchyme. <ref><pubmed>20201902</pubmed></ref> <br />
Studies involving neurogenesis demonstrated the sensitivity of Notch signaling to temporal and spatial cues and showed the early Notch signaling initially controls the number of cells with a neurogenic fate and later dictates the lineage decision of neural versus glial cell fate. <ref><pubmed>16429119</pubmed></ref><br />
Neural crest precursors for ideal patterning of the outflow tract are required in the Notch signaling pathway. The use of a dominant negative form of a master mind like protein (MAML) which has shown to be a pan Notch inhibitor in neural crest cells inactivates Notch signaling. This results in congenital heart defects like pulmonary artery stenosis and aortic arch patterning defects associated with defects in smooth muscle formation. <ref><pubmed> 17273555 </pubmed></ref><br />
Part of the phenotype in defective neural crest cells is attributed to loss of Notch2 signalling as Notch2 inactivation in these cells produces small caliber aortas and pulmonary arteries because of defects in smooth muscle. <ref><pubmed> 18330927 </pubmed></ref><br />
Jagged1 is the ligand involved which signals to Notch on neural crest cell surfaces to induce vascular smooth muscle cell differentiation. <ref><pubmed> 18245384 </pubmed></ref><br />
Mutations in both JAGGED1 and NOTCH2 genes have been known to cause Alagille syndrome, further substantiating the importance of this pathway in proper formation of the outflow tract. <ref><pubmed> 16575836 </pubmed></ref><br />
<br />
Another study by Garg stresses the importance of Notch signaling in the outflow tract region. NOTCH1 mutations were seen in patients with aortic stenosis. Aortic stenosis results from the calcification of the aortic valve and is quite common in adults. However, in children, this may result in failure of the left ventricle to develop properly. NOTCH1 haploinsufficiency is also linked to early calcification and bicuspid aortic valve disease. This could be due to an early induction of Runx2 through the HRT genes.<br />
<ref><pubmed> 16025100 </pubmed></ref><br />
<br />
<br><br><br />
<br />
====Central Nervous System====<br />
<br />
If you would like to generally learn about and become familiar with neural development in the embryo before reading this section, click [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Neural_Development here]!<br />
<br />
[[File:Notch CNS simple diagram.png|thumb|450px|right|alt=Simplified Diagram of Roles of Notch in Neuronal Differentiation|'''Simplified Diagram of Roles of Notch in Neuronal Differentiation'''. Notch influences the differentiation of embryonic stem cells into neural cells via signalling with RBP (recombining binding protein), cyclin D1 and Hes1. (This student-drawn image is based upon Figure 1 from Chuang, Tung and Lin's 2015 review: [https://www.ncbi.nlm.nih.gov/pubmed/25815127 ''Neural differentiation from embryonic stem cells in vitro: An overview of the signaling pathways'']<ref name="PMID25815127"><pubmed>25815127</pubmed></ref>)]]<br />
'''Early Neural Differentiation'''<br />
<br />
Notch plays a major role in promoting neural commitment of cells. Lowell and colleagues (2011) used genetic manipulation to discover that the phenotype of stem cells is not affected by constitutively activated Notch in mouse embryonic stem cells (mESCs), however, interfering with Notch signalling -for example by pharmacological means- did impede neural fate determination. This role required Notch signalling via fibroblast growth factor (FGF) receptors. Furthermore, the conservation of the Notch signalling pathway within pluripotent stem cells is implied due to the existence of Notch ligands in stromal cells in human embryonic stem cells (hESCs) that induce neural differentiation. <ref name=PMID16594731><pubmed>16594731</pubmed></ref><br />
<br />
Das and colleagues (2010) manipulated Notch protein levels during specific stages of neural differentiation and found that if Notch signalling pathways were activated during day 3 of neural development for 6 hours, cell proliferation was dramatically enhanced. This was attributed to the induction by Notch of cyclin D1 expression. Without Notch signalling during neural development, there was reduced cyclin D1 levels. Manipulation of mESCs to express a dominant negative form of cyclin D1 resulted in abrogation of cell proliferation stimulated by Notch. Overall these results imply a temporally-specific role for Notch in CNS development, and that it requires cyclin D1 as a signalling molecule.<ref name=PMID20887720><pubmed>20887720</pubmed></ref><br />
<br />
Hes1 has also been shown to play a Notch-mediated role in neural progenitor maintenance, which is essential for proper development since cells need to proliferate only during specific periods in the embryo for the correct number, cell type and function to result. Shimojo, Ohtsuka and Kageyama (2008) used real time imaging in mice to show that Notch induces oscillatory expression of ''Hes1'' and other Notch target genes to maintain the complex temporal organisation of events in neural development. They concluded that further research could elucidate more about Hes1 oscillations in regards to neural progenitor maintenance, proliferation and differentiation <ref name=PMID18400163><pubmed>18400163</pubmed></ref>.<br />
<br />
Lastly, as well as influencing neural progenitor differentiation, it has been found that Notch also impacts the development and maintenance of polarised neural structures in the embryo. This was concluded from a knockout study in mice that elucidated a role for RBP (recombining binding protein), downstream of Notch, in modulating neural differentiation and maintaining rosette structure (an experimental ''in vitro'' correlate used for neural tube development) <ref name=PMID23675446><pubmed>23675446</pubmed></ref>. The researchers concluded that RBP knockouts lacked canonical Notch signalling and as a result showed multiple neurulation defects.<br />
<br><br><br />
<br />
====Other Systems====<br />
<br />
As aforementioned, Notch plays a wide array of roles in embryonic development, the follow table summarises these roles by each organ system:<br />
<br />
<big>Summary Table of Examples of Notch Signalling in Developmental Processes</big> <small>(adapted from Table 1<ref name="PMID21828089">As reviewed by <pubmed>21828089</pubmed></ref>)</small><br />
{| class="pretty table"<br />
|-bgcolor="CEDFF2"<br />
| '''Organ/Tissue'''<br />
| '''Processes regulated by Notch'''<br />
|-bgcolor="F5FAFF" <br />
| Brain<br />
| Controls the balance between gliogenesis and neurogenesis; stem cell maintenance<ref><pubmed>21262462</pubmed></ref><ref>As reviewed by <pubmed>20816397</pubmed></ref>; organisation and maintenance of polarity during early development<ref name="PMID23675446"/><br />
|-<br />
| Craniofacial structures<br />
| Palate morphogenesis: loss of Notch signalling results in cleft palate, fusion of the tongue with the palatal shelves, and other craniofacial defects; also involved in tooth development<br />
|-bgcolor="F5FAFF"<br />
| Ear<br />
| Defines the presumptive sensory epithelium; determines hair cell and supporting cell fates<br />
|-<br />
| Esophagus<br />
| Regulates esophageal epithelial homeostasis<br />
|-bgcolor="F5FAFF"<br />
| Heart<br />
| Cardiac patterning, cardiomyocyte differentiation, valve development, ventricular trabeculation, outflow tract development<br />
|-<br />
| Intestine<br />
| Controls proliferation and differentiation, including absorptive vs. secretory cell fates<br />
|-bgcolor="F5FAFF"<br />
| Limbs<br />
| Apical ectodermal ridge (AER) formation and digit morphogenesis, especially regulation of apoptosis<br />
|-<br />
| Lungs<br />
| Lateral inhibition between tracheal cells prevents extra cells from assuming the lead position during tracheal branching morphogenesis<br />
|-bgcolor="F5FAFF"<br />
| Neural crest<br />
| Controls patterning of neural crest precursors for the outflow tract region of the heart; regulates the transition from Schwann cell precursor to Schwann cell, controls Schwann cell proliferation and inhibits myelination; controls melanocyte stem cell maintenance<br />
|-<br />
| Pancreas<br />
| Specifies endocrine cell differentiation through lateral inhibition: endocrine lineage cells inhibit endocrine differentiation of their neighboring cells; maintains pancreatic endocrine precursor cells, inhibits terminal acinar cell differentiation; controls pancreatic epithelium branching and bud size<br />
|-bgcolor="F5FAFF"<br />
| Skin<br />
| Regulates cell adhesion, control of proliferation, hair follicle or feather papillae differentiation and homeostasis<br />
|-<br />
| Thyroid<br />
| Regulates the numbers of thyrocyte and C-cell progenitors and regulates differentiation and endocrine function of thyrocytes and C-cells<ref><pubmed>21364918</pubmed></ref><br />
|-bgcolor="F5FAFF"<br />
| Vasculature<br />
| Regulates arteriovenous specification and differentiation in endothelial cells and vascular smooth muscle cells; regulates blood vessel sprouting and branching<br />
|}<br />
<br />
====Quiz Your Notch-Knowledge on Embryonic Development!====<br />
<br />
<quiz display=simple><br />
<br />
{ In the development of which organ does Notch exert lateral inhibition to differentiate endocrine cells?<br />
|type="()"}<br />
- &nbsp; The heart<br />
- &nbsp; The central nervous system<br />
- &nbsp; The skin<br />
+ &nbsp; The pancreas<br />
|| Remember, Notch signals endocrine lineage cells of the developing pancreas to inhibit endocrine differentiation of their neighbouring cells, known as lateral inhibition. Notch plays various roles in the heart, central nervous system and skin, but not in this way. <br />
</quiz><br />
<br><br />
<br />
===Roles in Animal Development===<br />
The Notch signalling pathway doesn't just play a significant role in human development, but also affects events such as neurogenesis and myogenesis in some animals (thus why these animals are often used as models for human development in research!). Read below for information on some of these roles for Notch.<br />
<br><br><br />
<br />
[[File:Notch animals.png|thumb|450px|right|alt=Animals Whose Developmental Processes are Affected by Notch.|'''Animals Whose Developmental Processes are Affected by Notch.''' This is a simplified representation of a few examples of the animals (Drosophila flies<ref name=PMID21447553><pubmed>21447553</pubmed></ref>, C. elegans<ref name=PMID18599512><pubmed>18599512</pubmed></ref>, and the zebrafish<ref><pubmed>23840804</pubmed></ref>) in which development is influenced by the Notch signalling pathway, and their scientific names.]]<br />
<br />
====''Drosophila melanogaster''====<br />
<br />
'''(The Fly)'''<br />
<br />
Unlike the four Notch paralogs in humans, only one Notch homolog is present in ''Drosophila''.<ref name="Introduction to Notch Signalling"/><br />
<br />
Both canonical and non-canonical Notch signalling are involved in the structural and physiological responses and functional plasticity of olfactory receptor neurons in reaction to prolonged odour exposure.<ref><pubmed>26986723</pubmed></ref><ref><pubmed>26011623</pubmed></ref> Research has also shown that Notch is crucial for the formation of longitudinal connections in the Drosophila CNS. Kuzina, Song, and Giniger (2011) created temperature-sensitive mutations of Notch genes that prevented the development of mature longitudinal axon tracts. Additionally, it was found that the Notch phenotype appears at the earliest stages of the development of longitudinal connections in the CNS by observing early stage 13 embryos.<ref name=PMID21447553><pubmed>21447553</pubmed></ref><br />
<br><br><br />
<br />
====''Caenorhabditis elegans''====<br />
<br />
'''(The Worm)'''<br />
<br />
The Notch pathway in ''C. elegans'' occurs throughout development in populations of equipotent cells for neuronal function in postmitotic differentiated neurons. In these postmitotic neurons, there is a specialised post-embryonic development stage knows as 'dauer'. The Notch pathway is activated when cell signalling downstream of the developmental decision enter dauer. The Notch receptor glp-1 and the ligand lag-2 are expressed in the dauer stage and aid in maintaining this stage. Another Notch receptor, lin-12, functions upstream of insulin signalling components to promote conditions for growth and enhance dauer recovery. <ref name=PMID18599512><pubmed>18599512</pubmed></ref><br />
<br><br><br />
<br />
====''Danio rerio''====<br />
<br />
'''(The Zebrafish)'''<br />
<br />
The expression of Notch in the myogenic region and apical ectodermal ridge (AER) of the developing zebrafish fin is similar to what has been observed in developing chicken and mouse limbs, which shows how highly conserved the role of Notch signalling is in the development of appendages in vertebrates. During zebrafish embryogenesis, the timing and positioning of fin formation are dependent on Notch signalling. Notch is also involved in the actual processes of fin formation, such as AER signalling, chondrogenic differentiation, and myogenesis. In zebrafish embryos with defective Notch signalling, it was observed that the skeletal muscle fibres were thin and fragmented and the structure of the sarcomeres was significantly compromised. <ref name="PMID23840804"><pubmed>23840804</pubmed></ref><br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Expand this for an image from this research study</big><br />
|-<br />
|[[File:Abnormal pectoral fins are formed in Notch signalling disrupted larvae.jpg|thumb|450px|right|alt=Abnormal pectoral fins are formed in Notch signalling disrupted larvae|'''Abnormal pectoral fins are formed in Notch signalling disrupted larvae.''' (A–F) Live pictures of 5 dpf larvae. (A’) A pectoral fin from a sibling embryo showing the cartilaginous endoskeletal disc with individualized cells surrounded by thin matrix deposits, the fin fold and the chleitrum (n = 17) (E, E’). A similar pectoral fin was found in a DMSO-treated embryo (n = 9). Pectoral fins of Notch signalling disrupted embryos such as mibta52b (n = 18) (B, B’), jagged2 (n = 10) (C, C’) and Su(H)1+2 (n = 12) (D, D’) morphants and DAPT-treated embryos (n = 10) (F, F’) showing disorganized endoskeletal disc cells. cl, chleitrum; ed, endoskeletal disc; ff, fin fold.<ref name="PMID23840804"/>]]<br />
|}<br />
<br><br><br />
<br />
====Quiz Your Notch-Knowledge on Animal Development!====<br />
<br />
<quiz display=simple><br />
<br />
{In which animal (as described in this section) has it been shown that defective notch signalling leads to thinning and fragmentation of skeletal muscle fibres?<br />
|type="()"}<br />
- &nbsp; Drosophila melanogaster<br />
- &nbsp; I don't know!<br />
- &nbsp; Caenorhabditis elegans<br />
+ &nbsp; Danio rerio<br />
|| Remember, it was observed in one study that the skeletal muscle fibres of zebrafish (Danio rerio) were thin and fragmented and the structure of their sarcomeres were significantly compromised.<ref><pubmed>23840804</pubmed></ref> <br />
</quiz><br />
<br />
===Summary of Functions of Proteins Involved in Notch Signalling <small>(adapted from Table 1<ref name="PMID17761886"><pubmed>17761886</pubmed></ref>)</small>===<br />
{| class="pretty table"<br />
|-bgcolor="a3bfb1"<br />
| '''Mammals'''<br />
| '''''Drosophila'''''<br />
| '''''C.elegans'''''<br />
| '''Function'''<br />
|-bgcolor="F5FFFA" <br />
| Notch 1-4<br />
| Notch<br />
| Lin-12, Glp-1<br />
| Single transmembrane receptor and transcription factor<br />
|-<br />
| Delta 1, Delta3-4, Jagged1-2<br />
| Delta, Serrate<br />
| APX-1, LAG-2, ARG-1, DSL-1<br />
| Single transmembrane ligands of the Notch receptor<br />
|-bgcolor="F5FFFA" <br />
| CBF1/RBPJK<br>Mastermind1-3<br />
| Su(H)<br>Mastermind<br />
| Lag-1<br>Lag-3<br />
| DNA-binding transcription factor<br>Transcriptional co-activator<br />
|-<br />
| Lunatic, manic, and radical Fringe<br />
| Fringe<br />
|<br />
| Modifies both Notch and its ligands<br />
|-bgcolor="F5FFFA" <br />
| ADAM10, ADAM17<br />
| Kuzbanian, Kuzbanian-like, TACE<br />
| SUP-17, ADM-4<br />
| Metalloproteases targeting S2 Notch cleavage sites<br />
|-<br />
| Presenilin 1-2, nicastrin, APH1, PEN2<br />
| Presenilin, nicastrin, APH1, PEN2<br />
| SEL-12, APH-1, APH-2, PEN2<br />
| Proteins of the γ-secretase complex, which targets Notch S3 and S4 cleavage sites<br />
|-bgcolor="F5FFFA" <br />
| Mind bomb, skeletrophin, neuralized 1-2<br />
| Mind bomb 1-2, neuralized<br />
| Y47D3A.22<br />
| E3 ubiquitin-protein ligases that targets Delta and Jagged/Serrate and regulate their endocytosis<br />
|}<br />
<br><br />
<br />
===Abnormalities in Notch Signalling===<br />
Mutations in Notch genes and hence defects in Notch signalling have been implicated in the pathogenesis of several inherited diseases in humans.<ref name="PMID23729744">As reviewed by <pubmed>23729744</pubmed></ref><ref name="PMID22306179">As reviewed by <pubmed>22306179</pubmed></ref> The diseases listed in this summary table are only a few examples and are described in more detail below.<br />
<br><br />
<br />
{| class="pretty table"<br />
|-bgcolor="CEDFF2" <br />
| '''Disease'''<br />
| '''Gene'''<br />
| '''Phenotype'''<br />
|-bgcolor="F5FAFF" <br />
| Alagille syndrome ([http://omim.org/entry/118450 OMIM118450], [http://omim.org/entry/610205 OMIM610205])<br />
| ''JAG1'', ''NOTCH2''<br />
| Developmental abnormalities of the heart, liver, eye, and skeleton. Neonatal jaundice and cholestasis are early symptoms.<br />
|-<br />
| CADASIL ([http://omim.org/entry/125310 OMIM125310])<br />
| ''NOTCH3''<br />
| Autosomal vascular disorders linked to ischemic strokes, dementia, and premature death.<br />
|-bgcolor="F5FAFF"<br />
| T-cell acute lymphoblastic leukaemia ([http://omim.org/entry/613065 OMIM613065])<br />
| ''NOTCH1'' (mutation in heterodimerization domain or PEST domain)<br />
| Tumour derived from T-cell progenitors. Symptoms include anaemia and enlargement of lymph nodes in the liver and/or spleen.<br />
|-<br />
| Spondylocostal dysostosis ([http://omim.org/entry/122600 OMIM122600])<br />
| ''DLL3'', Lunatic fringe<br />
| Vertebral segmentation defects as well as rib abnormalities.<br />
|}<br />
<br />
====Alagille Syndrome====<br />
Alagille syndrome (AGS) is an autosomal dominant, multisystem disorder that mainly affects the liver, heart, and kidney. Diagnostic characteristics of the disease include liver disease, cardiac disease, vertebral defects, eye conditions, and facial features, as well as renal and vascular abnormalities.<ref>As reviewed by <pubmed>26548814</pubmed></ref> Two variants of AGS, type 1 and type 2, have been identified, and each is related to different defects in the Notch pathway. In clinically diagnosed cases of AGS type 1 (which accounts for approximately 97% of all cases of AGS), a mutation in the gene encoding the Notch ligand Jagged1 (Jag1) has been identified as a contributing factor.<ref>As reviewed by <pubmed>11745040</pubmed></ref> In the much rarer AGS type 2, a mutation in the NOTCH2 gene has been implicated in the manifestation of AGS. The mechanisms by which mutations in JAG1 and NOTCH2 lead to pathogenesis of AGS are not well understood, but it is known that normal Notch signalling is important in angiogenesis. Therefore, it is thought that abnormal JAG1 or NOTCH2 will cause disruptions to the pathway that leads to the vascular disorders present in AGS. This is also evidenced by research that JAG1 knockout mice suffer premature death due to vascular defects.<ref>As reviewed by <pubmed>21934706</pubmed></ref> It is possible that AGS caused by a mutation in NOTCH2 alone will lead to a different presentation than AGS patients with mutated JAG1; however, this is still undergoing further research. It is also unclear why AGS type 2 occurs at a significantly lower incidence than AGS type 1.<ref><pubmed>16773578</pubmed></ref><br />
<br><br><br />
<br />
====Spondylocostal Dysostosis====<br />
Spondylocostal Dysostosis (SD) is a collective term for conditions characterised by anomalies relating to rib and spine. The vertebrae are fused and shaped abnormally which can result in scoliosis. Similarly, the ribs may also be fused together or in some cases completely missing. As a result, people with this condition have short trunk dwarfism where their bodies are short in stature but have normal length limbs. Genetic changes are known to cause SD. SD Type 1 is the most prevalent form of this disease which is caused by the mutation in the delta like canonical Notch ligand 3 (DLL3 gene).<ref><pubmed>10742114</pubmed></ref> DLL3 provides the information for making a protein that regulates the Notch signalling pathway. The DLL3 protein in conjunction with the Notch pathway is primarily responsible for preventing the fusion of future vertebrae in a process known as somite segmentation.<ref><pubmed>11236715</pubmed></ref> An interruption in the Notch pathway inhibits the somite segmentation resulting in abnormalities relating to the ribs and spine as seen in SD. 25 percent of SD arise from mutations in the identified genes and further research suggest that other genes involved in the Notch signalling pathway may also be related to SD.<br />
<br><br><br />
<br />
====Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)====<br />
CADASIL is an autosomal-dominant disease of the small to medium-sized arteries, mainly in the brain, that leads to dementia and disability in mid-life. The symptoms, age of onset, and prognosis are variable. Distinguishing symptoms include subcortical ischemic events (60-80% of cases), cognitive impairment (60% of late stage disease), migraines (30-40%), mood disturbances (30%), and apathy (40%).<ref name="PMID21045164"><pubmed>21045164</pubmed></ref><ref name="PMID20301673"><pubmed>20301673</pubmed></ref> Approximately 5-10% of CADASIL patients also experience seizures. The mean age of onset is 45 years of age and the disease duration is between 10–40 years. More than 95% of CADASIL cases present with pathogenic mutations in NOTCH3 (located on chromosome 19p13), specifically the epidermal growth factor-like repeat domain.<ref name="PMID20301673"/><ref><pubmed>24579972</pubmed></ref> The NOTCH3 gene is involved in the normal development of blood vessels in both fetal and adult brains. In adults, NOTCH3 is expressed in the smooth muscle cells of arteries.<ref name="PMID21045164"/> There is currently no effective treatment available for CADASIL.<br />
<br><br><br />
<br />
====Congenital Heart Defects====<br />
<br />
'''Aortic Valve Disease'''<br />
<br />
[[File:Aortic valve disease.jpg|thumb|450px|right|alt=Loss of NOTCH1 expression in proximity to calcific nodules in human aortic valves|'''Loss of NOTCH1 expression in proximity to calcific nodules in human aortic valves.''' (A) Representative sections from control (A,B) and diseased (C-F) aortic valve cusps. (B) is high magnification image of boxed area in (A) and (D,E) are higher magnification of region in (C) while image in (F) shows another calcified aortic valve. Expression of Notch1 intracellular domain (NICD) is found in the thickened fibrosa of diseased aortic valve (C,E) as compared to the acellular fibrosa of control valves (A,B). However, there is significant loss of NICD expression in cells residing adjacent to calcific nodules (D,F). The fibrosa is oriented upward in all panels, and scale bars equal 100 microns (B,D,E,F are at same magnification). Brown signal represents NICD expression while nuclei are counterstained in blue.<ref name="PMID22110751"><pubmed>22110751</pubmed></ref>]]<br />
<br />
Calcification of the aortic valve is a leading cause of adult heart disease. Mutations in NOTCH1 have been found to cause various aortic valve abnormalities, including the development of a bicuspid aortic valve (as opposed to tricuspid) and valve calcification.<br />
<br />
&emsp;&emsp;A study by Garg et al. (2005) looked at mouse embryos and the expression of ''Notch1'' during development. It was found that during normal embryonic development, ''Notch1'' was abundantly expressed in the outflow tract mesenchyme (which develops into the heart valves) and the endocardium, as well as in the endothelial layer and mesenchyme of the aortic valve leaflets at the time of arterial trunk septation. Abnormal ''Notch1'' led to the death of mice from vascular endothelial defects. Garg et al. then investigated whether NOTCH1 was involved in calcium deposition and therefore valve calcification. This is thought to be due to differentiation of valve cells into osteoblast-like cells. This leads to the upregulation of osteopontin, osteocalcin, and other osteoblast-specific genes, which is normally regulated by the transcription factor Runx2. Runx2 is known to be upregulated in animal models of valve calcification. Garg et al. found that Notch1 was capable of repressing Runx2 activation. Heart tissue and vasculature are normally abundant with the hairy-related transcriptional repressors Hrt1 and Hrt2 (also called Hey1 and Hey2), which are normally activated by Notch and are key mediators of the Notch pathway. Hrt1 and Hrt2 were both expressed in the endothelium of the mice aortic valve leaflets, the endocardium, and the vascular endothelium. They were found to inhibit the activation of osteoblast-specific genes by Runx2. It was thought that Hrt proteins can repress Runx2 by physical interaction as well as mediate Notch1 repression of Runx2. Therefore, a defect in Notch will cause upregulation of Runx2, due to the lack of repressor activity by Notch itself and the activation of the repressors Hrt1 and Hrt2. This leads to the expression of osteoblast genes that results in the differentiation of valvular cells into osteoblast-like cells and ultimately causes aortic valve calficiation.<ref><pubmed>16025100</pubmed></ref><br />
<br />
The picture to the right is a histological image of aortic valve disease from a study performed in rats investigating molecular changes that occurred when Notch signalling was suppressed in the aortic valve.<ref name="PMID22110751"/><br />
<br><br><br />
<br />
====Tumourigenesis====<br />
Notch has been shown to be involved in cancer development and can act as both an oncogene and a tumour suppressor gene.<ref>As reviewed by <pubmed>14570040</pubmed></ref><ref name="PMID23729744"/> Defective Notch signalling has been implicated in the pathogenesis of several human cancers, such as acute myelogenous leukemia (overexpression of Jagged1 and Notch1), multiple myeloma (overexpression of Jagged1/2 and Notch1/2), and B-cell–derived Hodgkin lymphoma (overexpression of Jagged1 and Notch1).<ref name="PMID16291593">As reviewed by <pubmed>16291593</pubmed></ref><br />
<br />
Elevated levels of Notch ligand proteins and/or mRNA have been observed in several cancers. Upregulated Jagged1 mRNA has been seen in human pancreatic cancer; Jagged1 protein overexpression has also been studied in prostate, cervix, and brain cancers. Cervical cancers have shown upregulated Jagged2 mRNA. Additionally, elevated Dll1 mRNA has been observed in cervical cancers, as well as in human brain cancers at both Dll1 mRNA and protein levels. Additionally, defective Notch receptor expression has been implicated in cancer as well. For example, elevated Notch1 protein expression has been found in cervical, colon, lung, pancreas, skin, and brain cancers. Protein overexpression of Notch3 and Notch4 has also been seen in malignant melanoma and pancreatic cancer.<ref name="PMID16291593"/><br />
<br />
Interestingly, research has shown that Notch signalling can also have a tumour-suppressive effect. Studies have indicated that Notch signalling can inhibit proliferation and even stimulate apoptosis in malignant B-cells. Furthermore, the Notch1 intracellular domain has also shown the ability to induce growth arrest and apoptosis in Hodgkin lymphoma and multiple myeloma cells.<ref name="PMID16291593"/><br />
<br><br><br />
<br />
'''T-Cell Acute Lymphoblastic Leukaemia'''<br><br />
T-cell acute lymphoblastic leukaemia (T-ALL) is an example of how abnormal Notch signalling can lead to the development of cancer. T-ALL is an aggressive childhood cancer of the immune system's T-cells. The NOTCH1 gene encodes the Notch1 receptor, which is involved in the determination of pluripotent cell progenitors to T-cells and the organisation of these cells in the developing thymus. Activating mutations in the extracellular domain and/or the C-terminal PEST domain of Notch1 have been identified in more than half of all cases of T-ALL.<ref><pubmed>15472075</pubmed></ref><br />
<br><br><br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Other Examples of Roles of Notch in Cancer <small>(adapted from ''Notch in disease''<ref name="PMID23729744"/>)</small><br />
|-<br />
|-bgcolor="a3bfb1"<br />
| '''Gene'''<br />
| '''Role of Notch'''<br />
| '''Disease'''<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br>''NOTCH2''<br />
| Oncogene<br>Tumour suppressor<br />
| Pancreatic ductal adenocarcinoma<br />
|-<br />
| ''NCSTN''<br>''MAML1''<br>''APH1A''<br>''NOTCH2''<br />
| Tumour suppressor<br />
| Chronic myelomonocytic leukaemia<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br />
| Oncogene<br />
| Chronic lymphocytic leukaemia<br />
|-<br />
| Activated NOTCH<br />
| Tumour suppressor<br />
| Hepatocellular carcinoma<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br>''NOTCH2''<br>''NOTCH3''<br />
| Tumour suppressor<br />
| Head and neck squamous cell carcinoma<br />
|-<br />
| NOTCH<br />
| Tumour suppressor<br />
| B-cell acute lymphoblastic leukaemia<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br />
| Oncogene<br />
| Non-small-cell lung cancer<br />
|-<br />
| ''NOTCH1''<br />
| Oncogene<br />
| T-cell acute lymphoblastic leukaemia<br />
|}<br />
<br><br />
<br />
====Quiz Your Notch-Knowledge on Abnormalities in Notch Signalling!====<br />
<br />
<quiz display=simple><br />
{ What is the name for the collection of rib and spine abnormalities that result from interruption in the Notch pathway that leads to inhibition of somite segmentation in the embryo?<br />
|type="()"}<br />
- &nbsp; Alagille Syndrome<br />
- &nbsp; T-cell acute lymphoblastic leukaemia<br />
+ &nbsp; Spondylocostal Dysostosis<br />
- &nbsp; CADASIL<br />
|| Remember, Spondylocostal Dysostosis is a collective term for conditions characterised by anomalies relating to rib and spine. Genetic changes lead to an interruption in the Notch pathway that inhibits the somite segmentation resulting in abnormalities relating to the ribs and spine. Alagille syndrome is an autosomal dominant, multisystem disorder that mainly affects the liver, heart, and kidney. T-cell acute lymphoblastic leukaemia is an aggressive childhood cancer of the immune system's T-cells. CADASIL is an autosomal-dominant disease of the small to medium-sized arteries, mainly in the brain, that leads to dementia and disability in mid-life.<br />
</quiz><br />
<br />
===Current Areas of Research and Future Directions===<br />
Notch has been identified as having a role in the development of several cancers, and therefore research has recently begun investigating the use of Notch inhibitors in cancer treatment.<ref>As reviewed by <pubmed>27732970</pubmed></ref> γ-secretase inhibitors (GSIs), which inhibit the normal cleavage of Notch at the cell membrane and hence NICD release, have been a popular area of research. In the specific case of desmoid tumours, it was observed that treatment GSIs resulted in decreases in NICD and Hes1 expression in the tumour cells. Overall, tumour cell migration and invasion were decreased and cell growth was also inhibited.<ref><pubmed>26349011</pubmed></ref> GSIs have also been shown to have an inhibitory growth effect on pancreatic, breast, and lung cancers, but unfortunately they also produce side effects ''in vivo''.<ref>As reviewed by <pubmed>27688721</pubmed></ref> Therefore continued study into GSIs is required to make them safe for human treatment. Ultimately, with ongoing research, it is possible that the Notch pathway will eventually become an effective therapeutic target for cancers.<br />
<br><br><br />
<br />
<big><b>To search and read recent PubMed research and review articles on Notch, click <u>[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=Notch here]</u>!</b></big><br />
<br><br><br />
<br />
===Want to Read More About Notch?===<br />
The [http://www.omim.org/ OMIM (Online Mendelian Inheritance in Man) database] contains extensive information about the Notch genes and associated proteins and is a great place to go if you want to find out more about the Notch pathway in humans! Click on these links to learn more about the Notch genes that encode the human receptors and ligands:<br />
<li>[http://www.omim.org/entry/190198 NOTCH1] | [http://www.omim.org/entry/600275 NOTCH2] | [http://www.omim.org/entry/600276 NOTCH3] | [http://www.omim.org/entry/164951 NOTCH4]<br />
<li>[http://www.omim.org/entry/601920 JAG1] | [http://www.omim.org/entry/602570 JAG2]<br />
<li>[http://www.omim.org/entry/606582 DLL1] | [http://www.omim.org/entry/602768 DLL3] | [http://www.omim.org/entry/605185 DLL4]<br />
<br><br><br />
<br />
You can also look at these papers for examples of reviews and research papers that reinforce the diversity of how the Notch pathway functions in organisms.<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch influences adult development as well!</big><br />
|-<br />
|Interestingly, Notch does not only play a role in human embryonic development, but has also been found to influence developmental processes after birth. One of these processes is neurogenesis, for example.<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159580/ '''Not(ch) just development: Notch signalling in the adult brain.'''] <br />
<br />
This review explains that the Notch signalling pathway, which is so often regarded as a major molecular player in development, actually has important functions related to neural cells in the adult. As you would have read in the [[#Abnormalities in Notch signalling| Abnormalities in Notch Signalling]] section, Notch abnormalities are involved in a number of diseases, which underlines its importance in maintaining adult brain function. Some highlights of this review are: Figure 2 provides a schematic representation of precise roles Notch activation can play in the adult brain; explanations of the ways that Notch influences brain plasticity; and the discussion of conflicting results of studies exploring the role of Notch in stroke recovery.<ref name=PMID21505516><pubmed>21505516</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch Modulation for Therapy</big><br />
|-<br />
|As you would have read in the [[#Abnormalities in Notch signalling| Abnormalities in Notch Signalling]] section, Notch can play different roles in cancer development. An interesting review further elucidates that modulation of Notch signalling is actually being investigated as a potential target for cancer therapy:<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704338/ '''Targeting the Notch signaling pathway in cancer therapeutics'''] <br />
<br />
This articles focuses on reviewing data emerging from recent research, explaining how Notch contributes to the development of a number of cancers, and then outlining the current focuses of investigations into how to therapeutically manipulate the Notch pathway. Some highlights from this review are: the detailed description of how Notch interacts with other signalling pathways such as Wnt and the signalling cytokine Interleukin-6; explanations of the seemingly conflicting roles of Notch as a tumour promoter and suppressor; and discussion of the findings of various Notch-related studies in cancer stem cells.<ref name=PMID26767041><pubmed>26767041</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch influences reproduction in worker honey bees!</big><br />
|-<br />
| In our [[#Roles in Animal Development| Roles in Animal Development]] section we discussed Notch in relation to a number of animals, however one that we did not cover was the worker honey bee, or ''Apis mellifera''. A recent study shows that Notch also plays a role in these honeybees!<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976197/ '''Notch signalling mediates reproductive constraint in the adult worker honeybee.'''] <br />
<br />
This research paper essentially concludes that in the worker honeybee Notch signalling constrains reproduction between males and females; they were the first team to elucidate a molecular mechanism underlying the link between adult ovary activity in bees and the presence of the queen bee. Some highlights from this unique and interesting study are: the background explanation that female worker bees have suppressed activity due to pheromones produced by the queen; the finding that Notch plays a part in this inactivation of reproductivity; and the discussion about social control of reproduction and evolution.<ref name=PMID27485026><pubmed>27485026</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch signalling is involved in embryo implantation!</big><br />
|-<br />
| Notch is essential for many developmental embryonic processes, as described in our [[#Roles in Embryonic Development|Roles in Embryonic Development]] section. Interestingly, research has shown that Notch signalling also has an important role in the initial process of establishing a successful pregnancy. Specifically, normal Notch signalling has been seen to be a critical factor in fetal-maternal communication during implantation and placentation. (To read more about these processes, go to these pages on [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Week_1_and_2_Development Weeks 1-2] and [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Week_3_Development Week 3] of development.)<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/24357662 '''Fetal-maternal communication: the role of Notch signalling in embryo implantation.''']<ref>As reviewed by <pubmed>24357662</pubmed></ref><br />
<br />
This review describes both human and animal studies of Notch signalling during pregnancy. It explains research of Notch signalling at the human blastocyst-maternal interface, and that Notch signalling has been observed in both the maternal endometrium and the blastocyst. Furthermore, Notch signalling is also important for the processes of implantation and placentation. Overall, the review summarises findings of Notch signalling in endometrial-trophectoderm interactions during the implantation, regulation of extravillous trophoblast invasion and spiral artery remodelling in the decidua, and angiogenesis in the placenta, as well as how abnormal Notch signalling is related with impaired placentation and pre-eclampsia.<br />
|}<br />
<br><br />
<br />
===Glossary===<br />
{| class="pretty table"<br />
|-<br />
| '''AER'''<br />
| 'Apical Ectodermal Ridge' is a structure that forms from the ectodermal cells at the distal end of each limb bud. The AER acts as a major signalling centre in order to ensure proper limb development.<br />
|-<br />
| '''Apoptosis'''<br />
| Programmed cell death which occurs in the development of many systems.<br />
|-<br />
| '''Calcification'''<br />
| The accumulation of calcium salts in body tissue. It normally occurs in the formation of bone, but abnormally calcium can be deposited in soft tissue causing it to harden.<br />
|-<br />
| '''Cardiogenic'''<br />
| From cardiogenesis - meaning formation of the heart.<br />
|-<br />
| '''Cardiomyocyte'''<br />
| The muscle cells (myocytes) that make up the cardiac muscle<br />
|-<br />
| '''Congenital'''<br />
| (Of a disease or physical abnormality) present from birth.<br />
|-<br />
| '''Craniofacial'''<br />
| Meaning relating to the cranium and the face.<br />
|-<br />
| '''Cyclin D1'''<br />
| A protein required for progression through the G1 phase of the cell cycle. Read more about it [https://en.wikipedia.org/wiki/Cyclin_D1 here], or see information on its encoding gene here: [http://omim.org/entry/168461 OMIM168461].<br />
|-<br />
| '''Endocardial'''<br />
| From endocardium - meaning the thin, smooth membrane which lines the inside of the chambers of the heart and forms the surface of the valves.<br />
|-<br />
| '''Endocrine'''<br />
| As in the endocrine system, refers to glands that secrete hormones or other substances directly into the blood.<br />
|-<br />
| '''Epithelium'''<br />
| The thin tissue that forms the outer layer of a body's surface and also lines the alimentary canal and other hollow structures.<br />
|-<br />
| '''Gastrulation'''<br />
| Describes the formative process of the formation of the trilaminar embryo containing the three germ layers.<br />
|-<br />
| '''Gliogenesis'''<br />
| The formation and development of glial cells (astrocytes, oligodendrocytes, Schwann cells, microglia).<br />
|-<br />
| '''Haematopoietic'''<br />
| From haematopoiesis - meaning the formation of blood cellular components<br />
|-<br />
| '''Haploinsufficiency'''<br />
| When a diploid organism has only a single functional copy of a gene (with the other copy inactivated by mutation), and so the total level of a gene product (a particular protein) produced by the cell is about half of the normal level.<br />
|-<br />
| '''Homeostasis'''<br />
| The ability to maintain a constant internal environment in response to environmental changes.<br />
|-<br />
| '''Ligand'''<br />
| A molecule that binds to a specific binding site on a protein (receptor).<br />
|-<br />
| '''Mef2C promoters'''<br />
| Myocyte-specific enhancer factor 2C is a transcription factor in the Mef2 family that is encoded by the gene ''MEF2C'' in humans ([https://omim.org/entry/600662 OMIM 600662]). This gene is involved in cardiac morphogenesis and myogenesis, as well as vascular development. It is thought to also possibly play a role in neurogenesis.<br />
|-<br />
| '''Mesenchymal'''<br />
| From mesenchyme - meaning a loosely organised, mainly mesodermal embryonic tissue which develops into connective and skeletal tissues, including blood and lymph.<br />
|-<br />
| '''Morphogenesis'''<br />
| Refers to the origin and development of morphological characteristics.<br />
|-<br />
| '''Myogenic'''<br />
| From myogenesis - meaning formation of muscle.<br />
|-<br />
| '''Myogenin'''<br />
| Also known as myogenic factor 4, this is a muscle-specific basic-helix-loop-helix transcription factor involved in the coordination of skeletal muscle development or myogenesis and repair.<br />
|-<br />
| '''Neural Crest'''<br />
| In vertebrate embryos, this is a transient structure that gives rise to most of the peripheral nervous system and to a number of non-neural cell types such as the smooth muscle cells of the cardiovascular system. <br />
|-<br />
| '''Neurogenic'''<br />
| From neurogenesis - meaning the formation of nervous tissue.<br />
|-<br />
| '''Neurulation'''<br />
| The folding process in vertebrate embryos whereby the neural plate transforms into the neural tube.<br />
|-<br />
| '''NICD'''<br />
| Notch intracellular domain<br />
|-<br />
| '''Oncogenic'''<br />
| From oncogenesis, also known as tumorigenesis or carcinogenesis - meaning the formation of a cancer, whereby normal cells are transformed into cancer cells.<br />
|-<br />
| '''Paracrine'''<br />
| A hormone that exerts an effect only in the vicinity of the gland secreting it.<br />
|-<br />
| '''Protease'''<br />
| An enzyme which breaks down proteins and peptides.<br />
|-<br />
| '''Runx2'''<br />
| Runt-related transcription factor 2 is a protein that in humans is encoded by the ''RUNX2'' gene ([http://omim.org/entry/600211 OMIM600211]). RUNX2 is an important transcription factor associated with osteoblast (bone substance-secreting cells) differentiation.<br />
|-<br />
| '''Stromal cells'''<br />
| The connective tissue cells of any organ. They support the function of the parenchymal cells of that organ. Fibroblasts and pericytes are among the most common types of stromal cells.<br />
|-<br />
|}<br />
<br />
====Further Glossary Links====<br />
[[A|A]] | [[B|B]] | [[C|C]] | [[D|D]] | [[E|E]] | [[F|F]] | [[G|G]] | [[H|H]] | [[I|I]] | [[J|J]] | [[K|K]] | [[L|L]] | [[M|M]] | [[N|N]] | [[O|O]] | [[P|P]] | [[Q|Q]] | [[R|R]] | [[S|S]] | [[T|T]] | [[U|U]] | [[V|V]] | [[W|W]] | [[X|X]] | [[Y|Y]] | [[Z|Z]] | [[Numbers|#]]<br />
<br />
===References===<br />
<references/></div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=2016_Group_Project_2&diff=255162
2016 Group Project 2
2016-10-27T07:53:06Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016header}}<br />
{{Group Assessment Criteria table}}<br />
<!-- Do not delete the above template from the Group project page. --><br />
=The Notch Signalling Pathway=<br />
===Introduction===<br />
The Notch signalling pathway is the most prevalent form of intracellular communication in multicellular organisms. It is a critical pathway for cell differentiation, proliferation, and apoptosis. It is involved in embryonic organ development through the regulation of cell-cell signalling; specifically lateral inhibition, formation of boundaries, and cell lineage assignation.<ref name="The Developing Human">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2015). The developing human: clinically oriented embryology (10th ed.). Philadelphia: Saunders.</ref><ref name="PMID10075488">As reviewed by <pubmed>10075488</pubmed></ref> This pathway is also actively involved in adjacent cell communication, developmental process such as adult homeostasis, and stem cell maintenance. Since this pathway is an intricate and crucial aspect of an organism's development and cell signalling, a mutation in the functional components of this pathway can cause a myriad of diseases such as congenital disorders, cancers, strokes, Alagille syndrome, and leukoencephalopathy.<ref name="PMID19255248">As reviewed by <pubmed>19255248</pubmed></ref> The process of Notch signalling primarily utilises a ligand-receptor interaction to release protein fragments at the cellular membrane, which then provide signals to the internal environment of the cell and to adjacent cells. In mammals, the Notch signalling pathway is comprised of four receptors (Notch 1-4) which interact with Delta or Jagged ligands to bring about the activation of this pathway. Homologous Notch genes have been identified in other animals, such as ''Drosophila melanogaster'' (fruit fly) and ''Danio rerio'' (zebrafish).<br />
<br><br />
<br />
<big>What will you find on this wiki page?</big><br />
<br />
This page is designed to provide an overview of such features of the Notch signalling pathway, but is in no way a complete resource for all Notch-related information (especially since this signalling pathway has such a wide array of activities in many organisms and the scientific understanding of it is continuously updating!). By reading this page you should come to a better understanding of Notch in regards to: general molecular mechanisms; embryonic development by systems; examples of animal development; abnormalities and disease; current and potential future research; as well as a couple of links to interesting articles for those who want to read more. There is a [[#Glossary| Glossary]] at the bottom of the page for better understanding of scientific terms used throughout this page, and readers are encouraged to 'expand' any collapsed information on the page to optimise their experience in reading about Notch. <br />
<br><br><br />
<div align="center"><html5media width="560" height="315">https://www.youtube.com/embed/axkDX0XZyN0</html5media></div><br />
<br><br />
<br />
===History===<br />
{| class="pretty table"<br />
|-bgcolor="FAF5FF" <br />
| 1914<br />
| First description of a "notch" defect (loss of tissue in the wing) in ''Drosophila'' by John S. Dexter, giving the gene its name<ref>Dexter, J. (1914). The Analysis of a Case of Continuous Variation in Drosophila by a Study of Its Linkage Relations. ''The American Naturalist'', 48(576), 712-758. Retrieved from http://www.jstor.org/stable/2455888</ref><br />
|-<br />
| 1917<br />
| First allele of ''Notch'' is identified by Thomas Hunt Morgan<ref>Morgan, T. H. (1917). The theory of the gene. ''The American Naturalist'', 51(609), 513-544.</ref><br />
|-bgcolor="FAF5FF" <br />
|-<br />
| 1930s<br />
| Donald F. Poulson conducts research into the involvement of ''Notch'' in development.<ref><pubmed>16588136</pubmed></ref> <br />
|-<br />
| 1958<br />
| An investigation by W.J. Welshons confirmed that the locus of Notch is contained within the 3C7 band of the X chromosome.<ref><pubmed>13635554</pubmed></ref><br />
|-bgcolor="FAF5FF" <br />
| 1983<br />
| DNA sequences belonging to the Notch locus cloned and determined that RNA is required for the function of the wild type Notch. Further insight developed into the function of Notch and its role in differentiation and regeneration.<br />
|-<br />
| 1986<br />
| The molecular analysis and sequence of the Notch locus was determined by Michael W. Young and his team. A relationship was identified between the protein encoded by the major Notch transcript and mammalian clotting and growth factors.<ref><pubmed>3097517</pubmed></ref><br />
|-bgcolor="FAF5FF" <br />
| 1989<br />
| Neurogenic loci "Delta" and "Mastermind" identified and research conducted to search for genes which may have an interaction with the Notch protein. It was confirmed that mutations in these loci will affect neurogenesis.<br />
|}<br />
<br />
===Overview of Molecular Mechanisms===<br />
Mammals possess a total of four ''Notch'' genes, with five genes for encoding the associated ligands, Delta-like and Jagged. The ''Notch'' genes each code for a single transmembrane receptor. Extracellularly, it contains epidermal growth factor (EGF)-like repeats for ligand interaction and Lin-12-Notch (LN) repeats for regulating the interactions between the extracellular and intracellular regions. Intracellularly, Notch has seven ankyrin (ANK) repeats and a transactivation domain (TAD), as well as a proline, glutamine, serine, threonine-rich (PEST) domain for degradation of Notch.<br />
<br><br><br />
[[File:Notch structure cartoon.jpg|thumb|700px|center|'''The structure of the Notch receptor.'''<ref name="PMID19255248"/> Extracellularly there are epidermal growth factor (EGF)-like repeats and Lin-12-Notch repeats (LNRs). The Notch intracellular domain (NICD) is made up of a rRBP-Jkappa-associated module (RAM) domain, ankyrin (ANK) repeats, and a proline, glutamine, serine, threonine-rich (PEST) domain. There are three sites for cleavage by enzymes: S1, S2, and S3/S4.]]<br />
<br />
====Canonical pathway====<br />
[[File:Overview of Notch signalling.png|thumb|500px|'''Summary of canonical Notch signalling.''' The interaction between Delta-like or Serrate ligands (DSL) and the Notch receptor on an adjacent cell initiates proteolytic cleavage of Notch and the release of the Notch intracellular domain (NICD). The NICD is then transported to the nucleus where it can induce transcription of Notch target genes by binding to specific proteins (MAM, CSL).<ref><pubmed>27404588</pubmed></ref>]]<br />
The canonical Notch pathway is unique in that it involves direct interaction between adjacent cells, as opposed to paracrine signalling, because both the Notch ligands and Notch receptors are transmembrane proteins found in the cell membrane. Furthermore, the lack of a secondary messenger or amplification process means that the Notch pathway has limited opportunities for regulation and must therefore be tightly controlled. Depending on its developmental and cellular context, activation or inhibition of the pathway can result in a variety of cellular responses, including cell death, proliferation, or differentiation.<ref name="Introduction to Notch Signalling">Yamamoto, S., Schulze, K.L. & Bellen, H.J. (2014). Introduction to Notch Signalling. ''Notch Signaling: Methods and Protocols''. Methods in Molecular Biology: 1187</ref><br />
<br><br><br />
Four Notch proteins are involved in the canonical pathway. NOTCH1 to NOTCH4 are single transmembrane receptors and can interact with a variety of ligands, including NOTCH ligands (e.g. Delta ligands) and Serrate ligands. There are three Delta ligands (Dll1, Dll3, and Dll4) and two Serrate ligands (Jagged1 and Jagged2) present in mammals.<ref name="Introduction to Notch Signalling"/> The binding between the Notch receptor and the ligand on the adjacent cell induces the release of the Notch intracellular domain (NICD) via a sequence of proteolytic reactions.<ref name="The Developing Human"/> Cell-cell interaction is therefore critical in the process of triggering Notch signalling.<br />
<br><br><br />
The interaction on the cell surface between Notch and its ligand on an adjacent cell causes the extracellular metalloprotease site (S2 site) to be exposed. The S2 site is then cleaved by transmembrane proteases belonging to the a disintegrin and metalloproteinase/tumour necrosis factor α converting enzyme (ADAM/TACE) family. The remaining Notch fragment subsequently undergoes two more intramembranous cleavages at the S3/S4 sites by the γ-secretase complex. Finally, the NICD is released and enters the nucleus to interact with CSL (CBF1, Suppressor of Hairless, Lag-1) and Mastermind-like proteins (MAMLs). CSL is a DNA-binding protein that acts as a transcription factor by forming repressor or activator complexes; in the absence of the NCID, CSL is bound to corepressor proteins (CoR) that prevent transcription of Notch target genes. MAMLs are transcriptional co-activators that are required for transcription of the target genes, hence they are involved in the regulation of the pathway.<ref name=PMID10075488/><ref name="Introduction to Notch Signalling"/> To stop signalling, the NICD is phosphorylated by kinases and ubiquitinated by E3 ubiquitin ligases, which results in proteasome mediated degradation and subsequent termination of the signal.<ref name="Introduction to Notch Signalling"/><br />
<br><br><br />
<br />
====Non-canonical pathway====<br />
Immense research has been carried out on the canonical Notch pathway and its members are well known. While canonical notch ligands control most of the known Notch signalling, a group of structurally distinct non-canonical ligands exist which activate Notch and its pleiotropic effects. Notch can non-canonically carry out its functions by post-translationally targeting Wnt/β-catenin signalling. This type of signalling is CSL-independent and can also work independently of ligands. Some genes are affected by the non-canonical Notch signalling, however their mediators in most cases are unknown. Notch binds and titrates levels of active β-catenin. Therefore, active β-catenin activity may serve as a useful readout for non-canonical Notch signals.<ref name="PMID22397947">As reviewed by <pubmed>22397947</pubmed></ref> <br />
<br />
Recent research has shown that Notch signalling plays crucial roles for cellular differentiation during development through γ-secretase-dependent intramembrane proteolysis followed by transcription of target genes. Hayashi et al. (2016) uncovered a ligand-dependent but γ-secretase-independent, non-canonical Notch signalling involved in presynaptic protein expression in postmitotic neurons.<ref name="PMID27040987"><pubmed>27040987</pubmed></ref><br />
<br><br><br />
<br />
====Transcriptional regulation of Notch signalling====<br />
A number of genes have been found to act as modulators of Notch signalling by modifying the ability of Notch to interact with its ligands. These include proteins acting extracellularly (Fringe, Brainiac, Egghead, Scabrous, Wingless), proteins acting at the cell membrane (Big brain), proteins acting intracellularly (Numb, Sanpodo, Disabled, Deltex, Dishevelled), and proteins acting within the nucleus (Hairless, EMB-5, Strawberry notch).<ref name="PMID9892565">As reviewed by <pubmed>9892565</pubmed></ref><br />
<br />
In ''Drosophila melanogaster'', it has been seen that ''fringe'' is able to affect the ability of Notch to be activated by the Serrate and Delta ligands. Specifically in the ''Drosophila'' wing, it was observed that Serrate did not interact with Notch in specific areas due to the action of ''fringe''<ref><pubmed>9247339</pubmed></ref>. Fringe is not required for initial Notch signalling, but is thought to be important for signalling processes when Notch activation occurs along the borders between distinct cell populations. Research suggests that Fringe specifically affects the binding between Notch and its ligands, rather than an activation step separate or subsequent to ligand binding. The ''brainiac'' and ''egghead'' genes are thought to either influence the production of a Notch ligand or act as substitute ligands themselves.<ref name="PMID9892565"/><br />
<br><br><br />
<br />
====Examples of Proteins Involved in Interaction with the Notch Intracellular Domain <small>(adapted from Table 3<ref name="PMID21828089"/>)</small>====<br />
{| class="pretty table"<br />
|-bgcolor="A3BFB1" <br />
| '''Protein'''<br />
| '''Interaction with NICD'''<br />
|-bgcolor="F5FFFA"<br />
| Adenamatous polyposis coli (Apc)<br />
| Controls Notch trafficking<br />
|-<br />
| Cyclin-dependant kinase 8 (CDK8)<br />
| Phosphorylates NICD to make it a substrate for ubiquitylation and degradation<br />
|-bgcolor="F5FFFA"<br />
| CBF1, Su(H) and LAG-1/Recombination signal binding protein for immunoglobulin kappa J region (CSL/RBP-J)<br />
| Main canonical transcriptional co-factor for NICD<br />
|-<br />
| Cyclin C (CycC)<br />
| Targets NICD for phosphorylation to make it a substrate for ubiquitylation and degradation<br />
|-bgcolor="F5FFFA"<br />
| Dishevelled (Dsh/Dvl)<br />
| Controls ligand-independent Notch trafficking; inhibits canonical Notch signalling<br />
|-<br />
| Deltex-1-4 (Dtx1-4)<br />
| Controls Notch ubiquitylation, processing, and internalisation<br />
|-bgcolor="F5FFFA"<br />
| Itchy, E3 ubiquitin protein ligase (Itch)<br />
| Promotes ubiquitylation of NICD<br />
|-<br />
| Mastermind-like 1/2 (Maml1/2)<br />
| Co-activator for NICD/CSL<br />
|-bgcolor="F5FFFA"<br />
| Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-ϰb)<br />
| NICD blocks NF-ϰb transcription of NF-ϰb target genes through binding to p50/cRel<br>NICD enhances NF-ϰb transcription of target genes by retaining NF-ϰb in the nucleus<br />
|-<br />
| Numb homolog (Numb)<br />
| Suppresses Notch signaling by recruiting E3 ubiquitin ligases to ubiquitylate Notch<br>Controls Notch trafficking during asymmetric cell division<br />
|-bgcolor="F5FFFA"<br />
| Smad family members (SMAD)<br />
| Smads enhance Notch signalling; Notch fine-tunes signalling through Smads<br />
|}<br />
<br><br />
<br />
===Roles in Embryonic Development===<br />
The phylogenetically conserved Notch signalling pathway plays a crucial role in the development of multiple organ systems, and is a major regulator of stem cell fate. It is responsible for the regulation of the transcription of a number of signalling molecules, such as ''MyoD'', ''Mash1'' and ''GATA2'', which are genes controlling the fate of myogenic, neurogenic and haematopoietic stem cells, respectively. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> The following subsections will further elucidate the vital roles of Notch signalling during normal embryonic development. If you would like to better understand human embryonic development before reading this section, [https://embryology.med.unsw.edu.au/embryology/index.php/Embryonic_Development| this page] serves as a great resource. <br />
<br><br><br />
<br />
====Cardiovascular====<br />
<br />
If you would like to generally learn about and become familiar with cardiac development in the embryo before reading this section, click [https://embryology.med.unsw.edu.au/embryology/index.php/ANAT2341_Lab_11_-_Heart here]!<br />
<br />
'''Cardiomyocyte Specification and Differentiation'''<br />
<br />
Expression during the appropriate window of the timeline of embryogenesis of Notch receptors, ligands and downstream effector molecules elucidates a role for the Notch pathway in the earliest stages of cardiac development. It has been found to restrict the expression of specific cardiogenic genes in a spatiotemporal manner and regulate cardiac field specification as early as during gastrulation. <ref name=PMID19580804><pubmed>19580804</pubmed></ref> Interestingly, Notch has been found to play both suppressive and promoting roles in cardiogenesis.<br />
<br />
For example, it has been shown that Notch suppresses cardiomyocyte cell fate specification during early cardiogenesis. This has been demonstrated through studies such as that carried out by Rones and colleagues (2000), which used activation and inhibition of Notch signaling in Xenopus. <ref name=PMID10934030><pubmed>10934030</pubmed></ref><br />
<br />
On the other hand, studies such as that by Boni et al. (2008) have found that Notch signalling may also promote myogenesis from cardiac progenitor cells. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> Cardiogenesis has also been promoted by downregulating Notch-1 activity in stem cells of embryos (Nemir et al., 2006).<ref name=PMID16690879><pubmed>16690879</pubmed></ref><br />
<br />
Despite the understanding that Notch signalling is crucial to embryonic myogenesis, the exact molecular mechanism remains elusive. Research by Buas and colleagues (2010) has explored such mechanisms by studying the Notch target, Hey1, which is known to suppress myogenic differentiation. They concluded that this inhibitory function of Hey1 is primarily mediated through binding near to myogenin and Mef2C promoters, which leads to cessation of target gene expression. <ref name=PMID19917614><pubmed>19917614</pubmed></ref><br />
<br />
[[File:Notch CVS simple diagram.png|thumb|500px|right|alt=Simplified Scheme of the Roles of Notch in Cardiac Development|'''Simplified Scheme of the Roles of Notch in Cardiac Development.''' Notch has been found to restrict the expression of specific cardiogenic genes in a spatiotemporal manner and regulate cardiac field specification early in development. Further after cardiac differentiation, Notch influences development of the AVC (atrioventricular canal), cardiac valves, ventricular trabeculae and the cardiac outflow tract. (This student-drawn image is based upon Figure 2 in the 2014 review by Zhou and Liu: [https://www.ncbi.nlm.nih.gov/pubmed/24345875 ''Role of Notch signaling in the mammalian heart.'']<ref name=PMID24345875><pubmed>24345875</pubmed></ref>)]]<br />
<br />
'''Development of the Atrioventricular Canal'''<br />
<br />
A study by Rutenberg et al. (2006) and another by Kokubo et al. (2007) implicate a role for Notch signaling in the region between the atria and the ventricles of the heart (the atrioventricular canal, or AVC).<ref name=PMID17021042><pubmed>17021042</pubmed></ref> <ref name=PMID17259303><pubmed>17259303</pubmed></ref> They used chicken and mouse models, respectively, to show that other signalling factors, ''Bmp2'' and ''Tbx2'', are restricted to the AVC region by Notch signalling during development. <br />
<br />
Furthermore, Watanabe and colleagues (2006) showed that deletion of Notch targets increases ''Bmp2'' expression and expansion of the AVC tissue, however other, non-Notch restrictive factors involved in AVC development are likely to exist.<ref name=PMID16554359><pubmed>16554359</pubmed></ref> <br />
<br />
'''Heart Valve Development'''<br />
<br />
In order for the heart valve to properly form in the embryo, endocardial to mesenchymal transformation (EMT) must occur. The Notch pathway, alongside Wnt and Bmp, has been found to regulate the process of EMT, defects in which can lead to congenital heart valve disease. Interestingly, Timmerman and colleagues (2004) demonstrated that this role of Notch may also promote oncogenic transformation. This team also showed that embryos exhibited abortive endocardial EMT if they were deficient in Notch signalling components in vivo and in vitro. <ref name=PMID14701881><pubmed>14701881</pubmed></ref> <br />
<br />
A more recent paper by Wang et al. (2013) further explored the underlying signalling processes and interrelationships of molecules that impact EMT. They found that Jagged1-Notch1 signalling in cells of the endocardium potentiates expression of Wnt4, which in turn carries out paracrine action on adjacent AVC tissue to upregulate Bmp2 expression and thus signal EMT. <ref name=PMID23560082><pubmed>23560082</pubmed></ref><br />
<br />
'''Trabeculation'''<br />
<br />
Trabeculation is the initial process of ventricular chamber development that forms a series of cardiomyocyte projections within the lumens of the ventricles of the heart (called trabeculae). Grego-Bessa and colleagues (2007) addressed the roles Notch plays in trabeculation through ''RBPJk'' (the gene product of which interacts with Notch) and ''Notch1'' gene manipulation. Mutants of these two genes showed perturbed expression and signalling of ''EphrinB2'', ''NRG1'' and ''BMP10'', alongside reduced proliferation of myocardiocytes. This research ultimately suggested that ''EphrinB2'' is a direct target of Notch in the endocardium that simultaneously requires the Notch-dependent action of BMP10 and NRG1 in order for ventricular myocardium proliferation and differentiation to occur normally. <ref name=PMID17336907><pubmed>17336907</pubmed></ref> Furthermore, the important process of trabeculation has recently been shown to be controlled by sequential Notch activation by an investigation by D’Amato et al. (2015). <ref name=PMID26641715><pubmed>26641715</pubmed></ref><br />
<br />
'''Development of the Outflow Tract'''<br />
<br />
About one third of congenital heart defects include malformations in the outflow tract which include the aorta, pulmonary arteries, aortic arch and ductus arteriosus. During cardiogenesis, neural crest cells interact with second heart field myocardium and endocardial mesenchyme. <ref><pubmed>20201902</pubmed></ref> <br />
Studies involving neurogenesis demonstrated the sensitivity of Notch signaling to temporal and spatial cues and showed the early Notch signaling initially controls the number of cells with a neurogenic fate and later dictates the lineage decision of neural versus glial cell fate. <ref><pubmed>16429119</pubmed></ref><br />
Neural crest precursors for ideal patterning of the outflow tract are required in the Notch signaling pathway. The use of a dominant negative form of a master mind like protein (MAML) which has shown to be a pan Notch inhibitor in neural crest cells inactivates Notch signaling. This results in congenital heart defects like pulmonary artery stenosis and aortic arch patterning defects associated with defects in smooth muscle formation. <ref><pubmed> 17273555 </pubmed></ref><br />
Part of the phenotype in defective neural crest cells is attributed to loss of Notch2 signalling as Notch2 inactivation in these cells produces small caliber aortas and pulmonary arteries because of defects in smooth muscle. <ref><pubmed> 18330927 </pubmed></ref><br />
Jagged1 is the ligand involved which signals to Notch on neural crest cell surfaces to induce vascular smooth muscle cell differentiation. <ref><pubmed> 18245384 </pubmed></ref><br />
Mutations in both JAGGED1 and NOTCH2 genes have been known to cause Alagille syndrome, further substantiating the importance of this pathway in proper formation of the outflow tract. <ref><pubmed> 16575836 </pubmed></ref><br />
<br />
Another study by Garg stresses the importance of Notch signaling in the outflow tract region. NOTCH1 mutations were seen in patients with aortic stenosis. Aortic stenosis results from the calcification of the aortic valve and is quite common in adults. However, in children, this may result in failure of the left ventricle to develop properly. NOTCH1 haploinsufficiency is also linked to early calcification and bicuspid aortic valve disease. This could be due to an early induction of Runx2 through the HRT genes.<br />
<ref><pubmed> 16025100 </pubmed></ref><br />
<br />
<br><br><br />
<br />
====Central Nervous System====<br />
<br />
If you would like to generally learn about and become familiar with neural development in the embryo before reading this section, click [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Neural_Development here]!<br />
<br />
[[File:Notch CNS simple diagram.png|thumb|450px|right|alt=Simplified Diagram of Roles of Notch in Neuronal Differentiation|'''Simplified Diagram of Roles of Notch in Neuronal Differentiation'''. Notch influences the differentiation of embryonic stem cells into neural cells via signalling with RBP (recombining binding protein), cyclin D1 and Hes1. (This student-drawn image is based upon Figure 1 from Chuang, Tung and Lin's 2015 review: [https://www.ncbi.nlm.nih.gov/pubmed/25815127 ''Neural differentiation from embryonic stem cells in vitro: An overview of the signaling pathways'']<ref name="PMID25815127"><pubmed>25815127</pubmed></ref>)]]<br />
'''Early Neural Differentiation'''<br />
<br />
Notch plays a major role in promoting neural commitment of cells. Lowell and colleagues (2011) used genetic manipulation to discover that the phenotype of stem cells is not affected by constitutively activated Notch in mouse embryonic stem cells (mESCs), however, interfering with Notch signalling -for example by pharmacological means- did impede neural fate determination. This role required Notch signalling via fibroblast growth factor (FGF) receptors. Furthermore, the conservation of the Notch signalling pathway within pluripotent stem cells is implied due to the existence of Notch ligands in stromal cells in human embryonic stem cells (hESCs) that induce neural differentiation. <ref name=PMID16594731><pubmed>16594731</pubmed></ref><br />
<br />
Das and colleagues (2010) manipulated Notch protein levels during specific stages of neural differentiation and found that if Notch signalling pathways were activated during day 3 of neural development for 6 hours, cell proliferation was dramatically enhanced. This was attributed to the induction by Notch of cyclin D1 expression. Without Notch signalling during neural development, there was reduced cyclin D1 levels. Manipulation of mESCs to express a dominant negative form of cyclin D1 resulted in abrogation of cell proliferation stimulated by Notch. Overall these results imply a temporally-specific role for Notch in CNS development, and that it requires cyclin D1 as a signalling molecule.<ref name=PMID20887720><pubmed>20887720</pubmed></ref><br />
<br />
Hes1 has also been shown to play a Notch-mediated role in neural progenitor maintenance, which is essential for proper development since cells need to proliferate only during specific periods in the embryo for the correct number, cell type and function to result. Shimojo, Ohtsuka and Kageyama (2008) used real time imaging in mice to show that Notch induces oscillatory expression of ''Hes1'' and other Notch target genes to maintain the complex temporal organisation of events in neural development. They concluded that further research could elucidate more about Hes1 oscillations in regards to neural progenitor maintenance, proliferation and differentiation <ref name=PMID18400163><pubmed>18400163</pubmed></ref>.<br />
<br />
Lastly, as well as influencing neural progenitor differentiation, it has been found that Notch also impacts the development and maintenance of polarised neural structures in the embryo. This was concluded from a knockout study in mice that elucidated a role for RBP (recombining binding protein), downstream of Notch, in modulating neural differentiation and maintaining rosette structure (an experimental ''in vitro'' correlate used for neural tube development) <ref name=PMID23675446><pubmed>23675446</pubmed></ref>. The researchers concluded that RBP knockouts lacked canonical Notch signalling and as a result showed multiple neurulation defects.<br />
<br><br><br />
<br />
====Other Systems====<br />
<br />
As aforementioned, Notch plays a wide array of roles in embryonic development, the follow table summarises these roles by each organ system:<br />
<br />
<big>Summary Table of Examples of Notch Signalling in Developmental Processes</big> <small>(adapted from Table 1<ref name="PMID21828089">As reviewed by <pubmed>21828089</pubmed></ref>)</small><br />
{| class="pretty table"<br />
|-bgcolor="CEDFF2"<br />
| '''Organ/Tissue'''<br />
| '''Processes regulated by Notch'''<br />
|-bgcolor="F5FAFF" <br />
| Brain<br />
| Controls the balance between gliogenesis and neurogenesis; stem cell maintenance<ref><pubmed>21262462</pubmed></ref><ref>As reviewed by <pubmed>20816397</pubmed></ref>; organisation and maintenance of polarity during early development<ref name="PMID23675446"/><br />
|-<br />
| Craniofacial structures<br />
| Palate morphogenesis: loss of Notch signalling results in cleft palate, fusion of the tongue with the palatal shelves, and other craniofacial defects; also involved in tooth development<br />
|-bgcolor="F5FAFF"<br />
| Ear<br />
| Defines the presumptive sensory epithelium; determines hair cell and supporting cell fates<br />
|-<br />
| Esophagus<br />
| Regulates esophageal epithelial homeostasis<br />
|-bgcolor="F5FAFF"<br />
| Heart<br />
| Cardiac patterning, cardiomyocyte differentiation, valve development, ventricular trabeculation, outflow tract development<br />
|-<br />
| Intestine<br />
| Controls proliferation and differentiation, including absorptive vs. secretory cell fates<br />
|-bgcolor="F5FAFF"<br />
| Limbs<br />
| Apical ectodermal ridge (AER) formation and digit morphogenesis, especially regulation of apoptosis<br />
|-<br />
| Lungs<br />
| Lateral inhibition between tracheal cells prevents extra cells from assuming the lead position during tracheal branching morphogenesis<br />
|-bgcolor="F5FAFF"<br />
| Neural crest<br />
| Controls patterning of neural crest precursors for the outflow tract region of the heart; regulates the transition from Schwann cell precursor to Schwann cell, controls Schwann cell proliferation and inhibits myelination; controls melanocyte stem cell maintenance<br />
|-<br />
| Pancreas<br />
| Specifies endocrine cell differentiation through lateral inhibition: endocrine lineage cells inhibit endocrine differentiation of their neighboring cells; maintains pancreatic endocrine precursor cells, inhibits terminal acinar cell differentiation; controls pancreatic epithelium branching and bud size<br />
|-bgcolor="F5FAFF"<br />
| Skin<br />
| Regulates cell adhesion, control of proliferation, hair follicle or feather papillae differentiation and homeostasis<br />
|-<br />
| Thyroid<br />
| Regulates the numbers of thyrocyte and C-cell progenitors and regulates differentiation and endocrine function of thyrocytes and C-cells<ref><pubmed>21364918</pubmed></ref><br />
|-bgcolor="F5FAFF"<br />
| Vasculature<br />
| Regulates arteriovenous specification and differentiation in endothelial cells and vascular smooth muscle cells; regulates blood vessel sprouting and branching<br />
|}<br />
<br />
====Quiz Your Notch-Knowledge on Embryonic Development!====<br />
<br />
<quiz display=simple><br />
<br />
{ In the development of which organ does Notch exert lateral inhibition to differentiate endocrine cells?<br />
|type="()"}<br />
- &nbsp; The heart<br />
- &nbsp; The central nervous system<br />
- &nbsp; The skin<br />
+ &nbsp; The pancreas<br />
|| Remember, Notch signals endocrine lineage cells of the developing pancreas to inhibit endocrine differentiation of their neighbouring cells, known as lateral inhibition. Notch plays various roles in the heart, central nervous system and skin, but not in this way. <br />
</quiz><br />
<br><br />
<br />
===Roles in Animal Development===<br />
The Notch signalling pathway doesn't just play a significant role in human development, but also affects events such as neurogenesis and myogenesis in some animals (thus why these animals are often used as models for human development in research!). Read below for information on some of these roles for Notch.<br />
<br><br><br />
<br />
[[File:Notch animals.png|thumb|450px|right|alt=Animals Whose Developmental Processes are Affected by Notch.|'''Animals Whose Developmental Processes are Affected by Notch.''' This is a simplified representation of a few examples of the animals (Drosophila flies<ref name=PMID21447553><pubmed>21447553</pubmed></ref>, C. elegans<ref name=PMID18599512><pubmed>18599512</pubmed></ref>, and the zebrafish<ref><pubmed>23840804</pubmed></ref>) in which development is influenced by the Notch signalling pathway, and their scientific names.]]<br />
<br />
====''Drosophila melanogaster''====<br />
<br />
'''(The Fly)'''<br />
<br />
Unlike the four Notch paralogs in humans, only one Notch homolog is present in ''Drosophila''.<ref name="Introduction to Notch Signalling"/><br />
<br />
Both canonical and non-canonical Notch signalling are involved in the structural and physiological responses and functional plasticity of olfactory receptor neurons in reaction to prolonged odour exposure.<ref><pubmed>26986723</pubmed></ref><ref><pubmed>26011623</pubmed></ref> Research has also shown that Notch is crucial for the formation of longitudinal connections in the Drosophila CNS. Kuzina, Song, and Giniger (2011) created temperature-sensitive mutations of Notch genes that prevented the development of mature longitudinal axon tracts. Additionally, it was found that the Notch phenotype appears at the earliest stages of the development of longitudinal connections in the CNS by observing early stage 13 embryos.<ref name=PMID21447553><pubmed>21447553</pubmed></ref><br />
<br><br><br />
<br />
====''Caenorhabditis elegans''====<br />
<br />
'''(The Worm)'''<br />
<br />
The Notch pathway in ''C. elegans'' occurs throughout development in populations of equipotent cells for neuronal function in postmitotic differentiated neurons. In these postmitotic neurons, there is a specialised post-embryonic development stage knows as 'dauer'. The Notch pathway is activated when cell signalling downstream of the developmental decision enter dauer. The Notch receptor glp-1 and the ligand lag-2 are expressed in the dauer stage and aid in maintaining this stage. Another Notch receptor, lin-12, functions upstream of insulin signalling components to promote conditions for growth and enhance dauer recovery. <ref name=PMID18599512><pubmed>18599512</pubmed></ref><br />
<br><br><br />
<br />
====''Danio rerio''====<br />
<br />
'''(The Zebrafish)'''<br />
<br />
The expression of Notch in the myogenic region and apical ectodermal ridge (AER) of the developing zebrafish fin is similar to what has been observed in developing chicken and mouse limbs, which shows how highly conserved the role of Notch signalling is in the development of appendages in vertebrates. During zebrafish embryogenesis, the timing and positioning of fin formation are dependent on Notch signalling. Notch is also involved in the actual processes of fin formation, such as AER signalling, chondrogenic differentiation, and myogenesis. In zebrafish embryos with defective Notch signalling, it was observed that the skeletal muscle fibres were thin and fragmented and the structure of the sarcomeres was significantly compromised. <ref name="PMID23840804"><pubmed>23840804</pubmed></ref><br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Expand this for an image from this research study</big><br />
|-<br />
|[[File:Abnormal pectoral fins are formed in Notch signalling disrupted larvae.jpg|thumb|450px|right|alt=Abnormal pectoral fins are formed in Notch signalling disrupted larvae|'''Abnormal pectoral fins are formed in Notch signalling disrupted larvae.''' (A–F) Live pictures of 5 dpf larvae. (A’) A pectoral fin from a sibling embryo showing the cartilaginous endoskeletal disc with individualized cells surrounded by thin matrix deposits, the fin fold and the chleitrum (n = 17) (E, E’). A similar pectoral fin was found in a DMSO-treated embryo (n = 9). Pectoral fins of Notch signalling disrupted embryos such as mibta52b (n = 18) (B, B’), jagged2 (n = 10) (C, C’) and Su(H)1+2 (n = 12) (D, D’) morphants and DAPT-treated embryos (n = 10) (F, F’) showing disorganized endoskeletal disc cells. cl, chleitrum; ed, endoskeletal disc; ff, fin fold.<ref name="PMID23840804"/>]]<br />
|}<br />
<br><br><br />
<br />
====Quiz Your Notch-Knowledge on Animal Development!====<br />
<br />
<quiz display=simple><br />
<br />
{In which animal (as described in this section) has it been shown that defective notch signalling leads to thinning and fragmentation of skeletal muscle fibres?<br />
|type="()"}<br />
- &nbsp; Drosophila melanogaster<br />
- &nbsp; I don't know!<br />
- &nbsp; Caenorhabditis elegans<br />
+ &nbsp; Danio rerio<br />
|| Remember, it was observed in one study that the skeletal muscle fibres of zebrafish (Danio rerio) were thin and fragmented and the structure of their sarcomeres were significantly compromised.<ref><pubmed>23840804</pubmed></ref> <br />
</quiz><br />
<br />
===Summary of Functions of Proteins Involved in Notch Signalling <small>(adapted from Table 1<ref name="PMID17761886"><pubmed>17761886</pubmed></ref>)</small>===<br />
{| class="pretty table"<br />
|-bgcolor="a3bfb1"<br />
| '''Mammals'''<br />
| '''''Drosophila'''''<br />
| '''''C.elegans'''''<br />
| '''Function'''<br />
|-bgcolor="F5FFFA" <br />
| Notch 1-4<br />
| Notch<br />
| Lin-12, Glp-1<br />
| Single transmembrane receptor and transcription factor<br />
|-<br />
| Delta 1, Delta3-4, Jagged1-2<br />
| Delta, Serrate<br />
| APX-1, LAG-2, ARG-1, DSL-1<br />
| Single transmembrane ligands of the Notch receptor<br />
|-bgcolor="F5FFFA" <br />
| CBF1/RBPJK<br>Mastermind1-3<br />
| Su(H)<br>Mastermind<br />
| Lag-1<br>Lag-3<br />
| DNA-binding transcription factor<br>Transcriptional co-activator<br />
|-<br />
| Lunatic, manic, and radical Fringe<br />
| Fringe<br />
|<br />
| Modifies both Notch and its ligands<br />
|-bgcolor="F5FFFA" <br />
| ADAM10, ADAM17<br />
| Kuzbanian, Kuzbanian-like, TACE<br />
| SUP-17, ADM-4<br />
| Metalloproteases targeting S2 Notch cleavage sites<br />
|-<br />
| Presenilin 1-2, nicastrin, APH1, PEN2<br />
| Presenilin, nicastrin, APH1, PEN2<br />
| SEL-12, APH-1, APH-2, PEN2<br />
| Proteins of the γ-secretase complex, which targets Notch S3 and S4 cleavage sites<br />
|-bgcolor="F5FFFA" <br />
| Mind bomb, skeletrophin, neuralized 1-2<br />
| Mind bomb 1-2, neuralized<br />
| Y47D3A.22<br />
| E3 ubiquitin-protein ligases that targets Delta and Jagged/Serrate and regulate their endocytosis<br />
|}<br />
<br><br />
<br />
===Abnormalities in Notch Signalling===<br />
Mutations in Notch genes and hence defects in Notch signalling have been implicated in the pathogenesis of several inherited diseases in humans.<ref name="PMID23729744">As reviewed by <pubmed>23729744</pubmed></ref><ref name="PMID22306179">As reviewed by <pubmed>22306179</pubmed></ref> The diseases listed in this summary table are only a few examples and are described in more detail below.<br />
<br><br />
<br />
{| class="pretty table"<br />
|-bgcolor="CEDFF2" <br />
| '''Disease'''<br />
| '''Gene'''<br />
| '''Phenotype'''<br />
|-bgcolor="F5FAFF" <br />
| Alagille syndrome ([http://omim.org/entry/118450 OMIM118450], [http://omim.org/entry/610205 OMIM610205])<br />
| ''JAG1'', ''NOTCH2''<br />
| Developmental abnormalities of the heart, liver, eye, and skeleton. Neonatal jaundice and cholestasis are early symptoms.<br />
|-<br />
| CADASIL ([http://omim.org/entry/125310 OMIM125310])<br />
| ''NOTCH3''<br />
| Autosomal vascular disorders linked to ischemic strokes, dementia, and premature death.<br />
|-bgcolor="F5FAFF"<br />
| T-cell acute lymphoblastic leukaemia ([http://omim.org/entry/613065 OMIM613065])<br />
| ''NOTCH1'' (mutation in heterodimerization domain or PEST domain)<br />
| Tumour derived from T-cell progenitors. Symptoms include anaemia and enlargement of lymph nodes in the liver and/or spleen.<br />
|-<br />
| Spondylocostal dysostosis ([http://omim.org/entry/122600 OMIM122600])<br />
| ''DLL3'', Lunatic fringe<br />
| Vertebral segmentation defects as well as rib abnormalities.<br />
|}<br />
<br />
====Alagille Syndrome====<br />
Alagille syndrome (AGS) is an autosomal dominant, multisystem disorder that mainly affects the liver, heart, and kidney. Diagnostic characteristics of the disease include liver disease, cardiac disease, vertebral defects, eye conditions, and facial features, as well as renal and vascular abnormalities.<ref>As reviewed by <pubmed>26548814</pubmed></ref> Two variants of AGS, type 1 and type 2, have been identified, and each is related to different defects in the Notch pathway. In clinically diagnosed cases of AGS type 1 (which accounts for approximately 97% of all cases of AGS), a mutation in the gene encoding the Notch ligand Jagged1 (Jag1) has been identified as a contributing factor.<ref>As reviewed by <pubmed>11745040</pubmed></ref> In the much rarer AGS type 2, a mutation in the NOTCH2 gene has been implicated in the manifestation of AGS. The mechanisms by which mutations in JAG1 and NOTCH2 lead to pathogenesis of AGS are not well understood, but it is known that normal Notch signalling is important in angiogenesis. Therefore, it is thought that abnormal JAG1 or NOTCH2 will cause disruptions to the pathway that leads to the vascular disorders present in AGS. This is also evidenced by research that JAG1 knockout mice suffer premature death due to vascular defects.<ref>As reviewed by <pubmed>21934706</pubmed></ref> It is possible that AGS caused by a mutation in NOTCH2 alone will lead to a different presentation than AGS patients with mutated JAG1; however, this is still undergoing further research. It is also unclear why AGS type 2 occurs at a significantly lower incidence than AGS type 1.<ref><pubmed>16773578</pubmed></ref><br />
<br><br><br />
<br />
====Spondylocostal Dysostosis====<br />
Spondylocostal Dysostosis (SD) is a collective term for conditions characterised by anomalies relating to rib and spine. The vertebrae are fused and shaped abnormally which can result in scoliosis. Similarly, the ribs may also be fused together or in some cases completely missing. As a result, people with this condition have short trunk dwarfism where their bodies are short in stature but have normal length limbs. Genetic changes are known to cause SD. SD Type 1 is the most prevalent form of this disease which is caused by the mutation in the delta like canonical Notch ligand 3 (DLL3 gene).<ref><pubmed>10742114</pubmed></ref> DLL3 provides the information for making a protein that regulates the Notch signalling pathway. The DLL3 protein in conjunction with the Notch pathway is primarily responsible for preventing the fusion of future vertebrae in a process known as somite segmentation.<ref><pubmed>11236715</pubmed></ref> An interruption in the Notch pathway inhibits the somite segmentation resulting in abnormalities relating to the ribs and spine as seen in SD. 25 percent of SD arise from mutations in the identified genes and further research suggest that other genes involved in the Notch signalling pathway may also be related to SD.<br />
<br><br><br />
<br />
====Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)====<br />
CADASIL is an autosomal-dominant disease of the small to medium-sized arteries, mainly in the brain, that leads to dementia and disability in mid-life. The symptoms, age of onset, and prognosis are variable. Distinguishing symptoms include subcortical ischemic events (60-80% of cases), cognitive impairment (60% of late stage disease), migraines (30-40%), mood disturbances (30%), and apathy (40%).<ref name="PMID21045164"><pubmed>21045164</pubmed></ref><ref name="PMID20301673"><pubmed>20301673</pubmed></ref> Approximately 5-10% of CADASIL patients also experience seizures. The mean age of onset is 45 years of age and the disease duration is between 10–40 years. More than 95% of CADASIL cases present with pathogenic mutations in NOTCH3 (located on chromosome 19p13), specifically the epidermal growth factor-like repeat domain.<ref name="PMID20301673"/><ref><pubmed>24579972</pubmed></ref> The NOTCH3 gene is involved in the normal development of blood vessels in both fetal and adult brains. In adults, NOTCH3 is expressed in the smooth muscle cells of arteries.<ref name="PMID21045164"/> There is currently no effective treatment available for CADASIL.<br />
<br><br><br />
<br />
====Congenital Heart Defects====<br />
<br />
'''Aortic Valve Disease'''<br />
<br />
[[File:Aortic valve disease.jpg|thumb|450px|right|alt=Loss of NOTCH1 expression in proximity to calcific nodules in human aortic valves|'''Loss of NOTCH1 expression in proximity to calcific nodules in human aortic valves.''' (A) Representative sections from control (A,B) and diseased (C-F) aortic valve cusps. (B) is high magnification image of boxed area in (A) and (D,E) are higher magnification of region in (C) while image in (F) shows another calcified aortic valve. Expression of Notch1 intracellular domain (NICD) is found in the thickened fibrosa of diseased aortic valve (C,E) as compared to the acellular fibrosa of control valves (A,B). However, there is significant loss of NICD expression in cells residing adjacent to calcific nodules (D,F). The fibrosa is oriented upward in all panels, and scale bars equal 100 microns (B,D,E,F are at same magnification). Brown signal represents NICD expression while nuclei are counterstained in blue.<ref name="PMID22110751"><pubmed>22110751</pubmed></ref>]]<br />
<br />
Calcification of the aortic valve is a leading cause of adult heart disease. Mutations in NOTCH1 have been found to cause various aortic valve abnormalities, including the development of a bicuspid aortic valve (as opposed to tricuspid) and valve calcification.<br />
<br />
&emsp;&emsp;A study by Garg et al. (2005) looked at mouse embryos and the expression of ''Notch1'' during development. It was found that during normal embryonic development, ''Notch1'' was abundantly expressed in the outflow tract mesenchyme (which develops into the heart valves) and the endocardium, as well as in the endothelial layer and mesenchyme of the aortic valve leaflets at the time of arterial trunk septation. Abnormal ''Notch1'' led to the death of mice from vascular endothelial defects. Garg et al. then investigated whether NOTCH1 was involved in calcium deposition and therefore valve calcification. This is thought to be due to differentiation of valve cells into osteoblast-like cells. This leads to the upregulation of osteopontin, osteocalcin, and other osteoblast-specific genes, which is normally regulated by the transcription factor Runx2. Runx2 is known to be upregulated in animal models of valve calcification. Garg et al. found that Notch1 was capable of repressing Runx2 activation. Heart tissue and vasculature are normally abundant with the hairy-related transcriptional repressors Hrt1 and Hrt2 (also called Hey1 and Hey2), which are normally activated by Notch and are key mediators of the Notch pathway. Hrt1 and Hrt2 were both expressed in the endothelium of the mice aortic valve leaflets, the endocardium, and the vascular endothelium. They were found to inhibit the activation of osteoblast-specific genes by Runx2. It was thought that Hrt proteins can repress Runx2 by physical interaction as well as mediate Notch1 repression of Runx2. Therefore, a defect in Notch will cause upregulation of Runx2, due to the lack of repressor activity by Notch itself and the activation of the repressors Hrt1 and Hrt2. This leads to the expression of osteoblast genes that results in the differentiation of valvular cells into osteoblast-like cells and ultimately causes aortic valve calficiation.<ref><pubmed>16025100</pubmed></ref><br />
<br />
The picture to the right is a histological image of aortic valve disease from a study performed in rats investigating molecular changes that occurred when Notch signalling was suppressed in the aortic valve.<ref name="PMID22110751"/><br />
<br><br><br />
<br />
====Tumourigenesis====<br />
Notch has been shown to be involved in cancer development and can act as both an oncogene and a tumour suppressor gene.<ref>As reviewed by <pubmed>14570040</pubmed></ref><ref name="PMID23729744"/> Defective Notch signalling has been implicated in the pathogenesis of several human cancers, such as acute myelogenous leukemia (overexpression of Jagged1 and Notch1), multiple myeloma (overexpression of Jagged1/2 and Notch1/2), and B-cell–derived Hodgkin lymphoma (overexpression of Jagged1 and Notch1).<ref name="PMID16291593">As reviewed by <pubmed>16291593</pubmed></ref><br />
<br />
Elevated levels of Notch ligand proteins and/or mRNA have been observed in several cancers. Upregulated Jagged1 mRNA has been seen in human pancreatic cancer; Jagged1 protein overexpression has also been studied in prostate, cervix, and brain cancers. Cervical cancers have shown upregulated Jagged2 mRNA. Additionally, elevated Dll1 mRNA has been observed in cervical cancers, as well as in human brain cancers at both Dll1 mRNA and protein levels. Additionally, defective Notch receptor expression has been implicated in cancer as well. For example, elevated Notch1 protein expression has been found in cervical, colon, lung, pancreas, skin, and brain cancers. Protein overexpression of Notch3 and Notch4 has also been seen in malignant melanoma and pancreatic cancer.<ref name="PMID16291593"/><br />
<br />
Interestingly, research has shown that Notch signalling can also have a tumour-suppressive effect. Studies have indicated that Notch signalling can inhibit proliferation and even stimulate apoptosis in malignant B-cells. Furthermore, the Notch1 intracellular domain has also shown the ability to induce growth arrest and apoptosis in Hodgkin lymphoma and multiple myeloma cells.<ref name="PMID16291593"/><br />
<br><br><br />
<br />
'''T-Cell Acute Lymphoblastic Leukaemia'''<br><br />
T-cell acute lymphoblastic leukaemia (T-ALL) is an example of how abnormal Notch signalling can lead to the development of cancer. T-ALL is an aggressive childhood cancer of the immune system's T-cells. The NOTCH1 gene encodes the Notch1 receptor, which is involved in the determination of pluripotent cell progenitors to T-cells and the organisation of these cells in the developing thymus. Activating mutations in the extracellular domain and/or the C-terminal PEST domain of Notch1 have been identified in more than half of all cases of T-ALL.<ref><pubmed>15472075</pubmed></ref><br />
<br><br><br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Other Examples of Roles of Notch in Cancer <small>(adapted from ''Notch in disease''<ref name="PMID23729744"/>)</small><br />
|-<br />
|-bgcolor="a3bfb1"<br />
| '''Gene'''<br />
| '''Role of Notch'''<br />
| '''Disease'''<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br>''NOTCH2''<br />
| Oncogene<br>Tumour suppressor<br />
| Pancreatic ductal adenocarcinoma<br />
|-<br />
| ''NCSTN''<br>''MAML1''<br>''APH1A''<br>''NOTCH2''<br />
| Tumour suppressor<br />
| Chronic myelomonocytic leukaemia<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br />
| Oncogene<br />
| Chronic lymphocytic leukaemia<br />
|-<br />
| Activated NOTCH<br />
| Tumour suppressor<br />
| Hepatocellular carcinoma<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br>''NOTCH2''<br>''NOTCH3''<br />
| Tumour suppressor<br />
| Head and neck squamous cell carcinoma<br />
|-<br />
| NOTCH<br />
| Tumour suppressor<br />
| B-cell acute lymphoblastic leukaemia<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br />
| Oncogene<br />
| Non-small-cell lung cancer<br />
|-<br />
| ''NOTCH1''<br />
| Oncogene<br />
| T-cell acute lymphoblastic leukaemia<br />
|}<br />
<br><br />
<br />
====Quiz Your Notch-Knowledge on Abnormalities in Notch Signalling!====<br />
<br />
<quiz display=simple><br />
{ What is the name for the collection of rib and spine abnormalities that result from interruption in the Notch pathway that leads to inhibition of somite segmentation in the embryo?<br />
|type="()"}<br />
- &nbsp; Alagille Syndrome<br />
- &nbsp; T-cell acute lymphoblastic leukaemia<br />
+ &nbsp; Spondylocostal Dysostosis<br />
- &nbsp; CADASIL<br />
|| Remember, Spondylocostal Dysostosis is a collective term for conditions characterised by anomalies relating to rib and spine. Genetic changes lead to an interruption in the Notch pathway that inhibits the somite segmentation resulting in abnormalities relating to the ribs and spine. Alagille syndrome is an autosomal dominant, multisystem disorder that mainly affects the liver, heart, and kidney. T-cell acute lymphoblastic leukaemia is an aggressive childhood cancer of the immune system's T-cells. CADASIL is an autosomal-dominant disease of the small to medium-sized arteries, mainly in the brain, that leads to dementia and disability in mid-life.<br />
</quiz><br />
<br />
===Current Areas of Research and Future Directions===<br />
Notch has been identified as having a role in the development of several cancers, and therefore research has recently begun investigating the use of Notch inhibitors in cancer treatment.<ref>As reviewed by <pubmed>27732970</pubmed></ref> γ-secretase inhibitors (GSIs), which inhibit the normal cleavage of Notch at the cell membrane and hence NICD release, have been a popular area of research. In the specific case of desmoid tumours, it was observed that treatment GSIs resulted in decreases in NICD and Hes1 expression in the tumour cells. Overall, tumour cell migration and invasion were decreased and cell growth was also inhibited.<ref><pubmed>26349011</pubmed></ref> GSIs have also been shown to have an inhibitory growth effect on pancreatic, breast, and lung cancers, but unfortunately they also produce side effects ''in vivo''.<ref>As reviewed by <pubmed>27688721</pubmed></ref> Therefore continued study into GSIs is required to make them safe for human treatment. Ultimately, with ongoing research, it is possible that the Notch pathway will eventually become an effective therapeutic target for cancers.<br />
<br><br><br />
<br />
<big><b>To search and read recent PubMed research and review articles on Notch, click <u>[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=Notch here]</u>!</b></big><br />
<br><br><br />
<br />
===Want to Read More About Notch?===<br />
The [http://www.omim.org/ OMIM (Online Mendelian Inheritance in Man) database] contains extensive information about the Notch genes and associated proteins and is a great place to go if you want to find out more about the Notch pathway in humans! Click on these links to learn more about the Notch genes that encode the human receptors and ligands:<br />
<li>[http://www.omim.org/entry/190198 NOTCH1] | [http://www.omim.org/entry/600275 NOTCH2] | [http://www.omim.org/entry/600276 NOTCH3] | [http://www.omim.org/entry/164951 NOTCH4]<br />
<li>[http://www.omim.org/entry/601920 JAG1] | [http://www.omim.org/entry/602570 JAG2]<br />
<li>[http://www.omim.org/entry/606582 DLL1] | [http://www.omim.org/entry/602768 DLL3] | [http://www.omim.org/entry/605185 DLL4]<br />
<br><br><br />
<br />
You can also look at these papers for examples of reviews and research papers that reinforce the diversity of how the Notch pathway functions in organisms.<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch influences adult development as well!</big><br />
|-<br />
|Interestingly, Notch does not only play a role in human embryonic development, but has also been found to influence developmental processes after birth. One of these processes is neurogenesis, for example.<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159580/ '''Not(ch) just development: Notch signalling in the adult brain.'''] <br />
<br />
This review explains that the Notch signalling pathway, which is so often regarded as a major molecular player in development, actually has important functions related to neural cells in the adult. As you would have read in the [[#Abnormalities in Notch signalling| Abnormalities in Notch Signalling]] section, Notch abnormalities are involved in a number of diseases, which underlines its importance in maintaining adult brain function. Some highlights of this review are: Figure 2 provides a schematic representation of precise roles Notch activation can play in the adult brain; explanations of the ways that Notch influences brain plasticity; and the discussion of conflicting results of studies exploring the role of Notch in stroke recovery.<ref name=PMID21505516><pubmed>21505516</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch Modulation for Therapy</big><br />
|-<br />
|As you would have read in the [[#Abnormalities in Notch signalling| Abnormalities in Notch Signalling]] section, Notch can play different roles in cancer development. An interesting review further elucidates that modulation of Notch signalling is actually being investigated as a potential target for cancer therapy:<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704338/ '''Targeting the Notch signaling pathway in cancer therapeutics'''] <br />
<br />
This articles focuses on reviewing data emerging from recent research, explaining how Notch contributes to the development of a number of cancers, and then outlining the current focuses of investigations into how to therapeutically manipulate the Notch pathway. Some highlights from this review are: the detailed description of how Notch interacts with other signalling pathways such as Wnt and the signalling cytokine Interleukin-6; explanations of the seemingly conflicting roles of Notch as a tumour promoter and suppressor; and discussion of the findings of various Notch-related studies in cancer stem cells.<ref name=PMID26767041><pubmed>26767041</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch influences reproduction in worker honey bees!</big><br />
|-<br />
| In our [[#Roles in Animal Development| Roles in Animal Development]] section we discussed Notch in relation to a number of animals, however one that we did not cover was the worker honey bee, or ''Apis mellifera''. A recent study shows that Notch also plays a role in these honeybees!<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976197/ '''Notch signalling mediates reproductive constraint in the adult worker honeybee.'''] <br />
<br />
This research paper essentially concludes that in the worker honeybee Notch signalling constrains reproduction between males and females; they were the first team to elucidate a molecular mechanism underlying the link between adult ovary activity in bees and the presence of the queen bee. Some highlights from this unique and interesting study are: the background explanation that female worker bees have suppressed activity due to pheromones produced by the queen; the finding that Notch plays a part in this inactivation of reproductivity; and the discussion about social control of reproduction and evolution.<ref name=PMID27485026><pubmed>27485026</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch signalling is involved in embryo implantation!</big><br />
|-<br />
| Notch is essential for many developmental embryonic processes, as described in our [[#Roles in Embryonic Development|Roles in Embryonic Development]] section. Interestingly, research has shown that Notch signalling also has an important role in the initial process of establishing a successful pregnancy. Specifically, normal Notch signalling has been seen to be a critical factor in fetal-maternal communication during implantation and placentation. (To read more about these processes, go to these pages on [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Week_1_and_2_Development Weeks 1-2] and [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Week_3_Development Week 3] of development.)<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/24357662 '''Fetal-maternal communication: the role of Notch signalling in embryo implantation.''']<ref>As reviewed by <pubmed>24357662</pubmed></ref><br />
<br />
This review describes both human and animal studies of Notch signalling during pregnancy. It explains research of Notch signalling at the human blastocyst-maternal interface, and that Notch signalling has been observed in both the maternal endometrium and the blastocyst. Furthermore, Notch signalling is also important for the processes of implantation and placentation. Overall, the review summarises findings of Notch signalling in endometrial-trophectoderm interactions during the implantation, regulation of extravillous trophoblast invasion and spiral artery remodelling in the decidua, and angiogenesis in the placenta, as well as how abnormal Notch signalling is related with impaired placentation and pre-eclampsia.<br />
|}<br />
<br><br />
<br />
===Glossary===<br />
{| class="pretty table"<br />
|-<br />
| '''AER'''<br />
| 'Apical Ectodermal Ridge' is a structure that forms from the ectodermal cells at the distal end of each limb bud. The AER acts as a major signalling centre in order to ensure proper limb development.<br />
|-<br />
| '''Apoptosis'''<br />
| Programmed cell death which occurs in the development of many systems.<br />
|-<br />
| '''Calcification'''<br />
| The accumulation of calcium salts in body tissue. It normally occurs in the formation of bone, but abnormally calcium can be deposited in soft tissue causing it to harden.<br />
|-<br />
| '''Cardiogenic'''<br />
| From cardiogenesis - meaning formation of the heart.<br />
|-<br />
| '''Cardiomyocyte'''<br />
| The muscle cells (myocytes) that make up the cardiac muscle<br />
|-<br />
| '''Congenital'''<br />
| (Of a disease or physical abnormality) present from birth.<br />
|-<br />
| '''Craniofacial'''<br />
| Meaning relating to the cranium and the face.<br />
|-<br />
| '''Cyclin D1'''<br />
| A protein required for progression through the G1 phase of the cell cycle. Read more about it [https://en.wikipedia.org/wiki/Cyclin_D1 here], or see information on its encoding gene here: [http://omim.org/entry/168461 OMIM168461].<br />
|-<br />
| '''Endocardial'''<br />
| From endocardium - meaning the thin, smooth membrane which lines the inside of the chambers of the heart and forms the surface of the valves.<br />
|-<br />
| '''Endocrine'''<br />
| As in the endocrine system, refers to glands that secrete hormones or other substances directly into the blood.<br />
|-<br />
| '''Epithelium'''<br />
| The thin tissue that forms the outer layer of a body's surface and also lines the alimentary canal and other hollow structures.<br />
|-<br />
| '''Gastrulation'''<br />
| Describes the formative process of the formation of the trilaminar embryo containing the three germ layers.<br />
|-<br />
| '''Gliogenesis'''<br />
| The formation and development of glial cells (astrocytes, oligodendrocytes, Schwann cells, microglia).<br />
|-<br />
| '''Haematopoietic'''<br />
| From haematopoiesis - meaning the formation of blood cellular components<br />
|-<br />
| '''Haploinsufficiency'''<br />
| When a diploid organism has only a single functional copy of a gene (with the other copy inactivated by mutation), and so the total level of a gene product (a particular protein) produced by the cell is about half of the normal level.<br />
|-<br />
| '''Homeostasis'''<br />
| The ability to maintain a constant internal environment in response to environmental changes.<br />
|-<br />
| '''Ligand'''<br />
| A molecule that binds to a specific binding site on a protein (receptor).<br />
|-<br />
| '''Mef2C promoters'''<br />
| Myocyte-specific enhancer factor 2C is a transcription factor in the Mef2 family that is encoded by the gene ''MEF2C'' in humans ([https://omim.org/entry/600662 OMIM 600662]). This gene is involved in cardiac morphogenesis and myogenesis, as well as vascular development. It is thought to also possibly play a role in neurogenesis.<br />
|-<br />
| '''Mesenchymal'''<br />
| From mesenchyme - meaning a loosely organised, mainly mesodermal embryonic tissue which develops into connective and skeletal tissues, including blood and lymph.<br />
|-<br />
| '''Morphogenesis'''<br />
| Refers to the origin and development of morphological characteristics.<br />
|-<br />
| '''Myogenic'''<br />
| From myogenesis - meaning formation of muscle.<br />
|-<br />
| '''Myogenin'''<br />
| Also known as myogenic factor 4, this is a muscle-specific basic-helix-loop-helix transcription factor involved in the coordination of skeletal muscle development or myogenesis and repair.<br />
|-<br />
| '''Neural Crest'''<br />
| In vertebrate embryos, this is a transient structure that gives rise to most of the peripheral nervous system and to a number of non-neural cell types such as the smooth muscle cells of the cardiovascular system. <br />
|-<br />
| '''Neurogenic'''<br />
| From neurogenesis - meaning the formation of nervous tissue.<br />
|-<br />
| '''Neurulation'''<br />
| The folding process in vertebrate embryos whereby the neural plate transforms into the neural tube.<br />
|-<br />
| '''NICD'''<br />
| Notch intracellular domain<br />
|-<br />
| '''Oncogenic'''<br />
| From oncogenesis, also known as tumorigenesis or carcinogenesis - meaning the formation of a cancer, whereby normal cells are transformed into cancer cells.<br />
|-<br />
| '''Paracrine'''<br />
| A hormone that exerts an effect only in the vicinity of the gland secreting it.<br />
|-<br />
| '''Protease'''<br />
| An enzyme which breaks down proteins and peptides.<br />
|-<br />
| '''Runx2'''<br />
| Runt-related transcription factor 2 is a protein that in humans is encoded by the ''RUNX2'' gene ([http://omim.org/entry/600211 OMIM600211]). RUNX2 is an important transcription factor associated with osteoblast (bone substance-secreting cells) differentiation.<br />
|-<br />
| '''Stromal cells'''<br />
| The connective tissue cells of any organ. They support the function of the parenchymal cells of that organ. Fibroblasts and pericytes are among the most common types of stromal cells.<br />
|-<br />
|}<br />
<br />
====Further Glossary Links====<br />
[[A|A]] | [[B|B]] | [[C|C]] | [[D|D]] | [[E|E]] | [[F|F]] | [[G|G]] | [[H|H]] | [[I|I]] | [[J|J]] | [[K|K]] | [[L|L]] | [[M|M]] | [[N|N]] | [[O|O]] | [[P|P]] | [[Q|Q]] | [[R|R]] | [[S|S]] | [[T|T]] | [[U|U]] | [[V|V]] | [[W|W]] | [[X|X]] | [[Y|Y]] | [[Z|Z]] | [[Numbers|#]]<br />
<br />
===References===<br />
<references/></div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=2016_Group_Project_2&diff=255152
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2016-10-27T07:51:11Z
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<hr />
<div>{{ANAT2341Project2016header}}<br />
{{Group Assessment Criteria table}}<br />
<!-- Do not delete the above template from the Group project page. --><br />
=The Notch Signalling Pathway=<br />
===Introduction===<br />
The Notch signalling pathway is the most prevalent form of intracellular communication in multicellular organisms. It is a critical pathway for cell differentiation, proliferation, and apoptosis. It is involved in embryonic organ development through the regulation of cell-cell signalling; specifically lateral inhibition, formation of boundaries, and cell lineage assignation.<ref name="The Developing Human">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2015). The developing human: clinically oriented embryology (10th ed.). Philadelphia: Saunders.</ref><ref name="PMID10075488">As reviewed by <pubmed>10075488</pubmed></ref> This pathway is also actively involved in adjacent cell communication, developmental process such as adult homeostasis, and stem cell maintenance. Since this pathway is an intricate and crucial aspect of an organism's development and cell signalling, a mutation in the functional components of this pathway can cause a myriad of diseases such as congenital disorders, cancers, strokes, Alagille syndrome, and leukoencephalopathy.<ref name="PMID19255248">As reviewed by <pubmed>19255248</pubmed></ref> The process of Notch signalling primarily utilises a ligand-receptor interaction to release protein fragments at the cellular membrane, which then provide signals to the internal environment of the cell and to adjacent cells. In mammals, the Notch signalling pathway is comprised of four receptors (Notch 1-4) which interact with Delta or Jagged ligands to bring about the activation of this pathway. Homologous Notch genes have been identified in other animals, such as ''Drosophila melanogaster'' (fruit fly) and ''Danio rerio'' (zebrafish).<br />
<br><br />
<br />
<big>What will you find on this wiki page?</big><br />
<br />
This page is designed to provide an overview of such features of the Notch signalling pathway, but is in no way a complete resource for all Notch-related information (especially since this signalling pathway has such a wide array of activities in many organisms and the scientific understanding of it is continuously updating!). By reading this page you should come to a better understanding of Notch in regards to: general molecular mechanisms; embryonic development by systems; examples of animal development; abnormalities and disease; current and potential future research; as well as a couple of links to interesting articles for those who want to read more. There is a [[#Glossary| Glossary]] at the bottom of the page for better understanding of scientific terms used throughout this page, and readers are encouraged to 'expand' any collapsed information on the page to optimise their experience in reading about Notch. <br />
<br><br><br />
<div align="center"><html5media width="560" height="315">https://www.youtube.com/embed/axkDX0XZyN0</html5media></div><br />
<br><br />
<br />
===History===<br />
{| class="pretty table"<br />
|-bgcolor="FAF5FF" <br />
| 1914<br />
| First description of a "notch" defect (loss of tissue in the wing) in ''Drosophila'' by John S. Dexter, giving the gene its name<ref>Dexter, J. (1914). The Analysis of a Case of Continuous Variation in Drosophila by a Study of Its Linkage Relations. ''The American Naturalist'', 48(576), 712-758. Retrieved from http://www.jstor.org/stable/2455888</ref><br />
|-<br />
| 1917<br />
| First allele of ''Notch'' is identified by Thomas Hunt Morgan<ref>Morgan, T. H. (1917). The theory of the gene. ''The American Naturalist'', 51(609), 513-544.</ref><br />
|-bgcolor="FAF5FF" <br />
| 1930s<br />
| Donald F. Poulson conducts research into the involvement of ''Notch'' in development.<ref><pubmed>16588136</pubmed></ref><br />
|-<br />
| 1958<br />
| An investigation by W.J. Welshons confirmed that the locus of Notch is contained within the 3C7 band of the X chromosome.<ref><pubmed>13635554</pubmed></ref><br />
|-bgcolor="FAF5FF" <br />
| 1983<br />
| DNA sequences belonging to the Notch locus cloned and determined that RNA is required for the function of the wild type Notch. Further insight developed into the function of Notch and its role in differentiation and regeneration.<br />
|-<br />
| 1986<br />
| The molecular analysis and sequence of the Notch locus was determined by Michael W. Young and his team. A relationship was identified between the protein encoded by the major Notch transcript and mammalian clotting and growth factors.<ref><pubmed>3097517</pubmed></ref><br />
|-bgcolor="FAF5FF" <br />
| 1989<br />
| Neurogenic loci "Delta" and "Mastermind" identified and research conducted to search for genes which may have an interaction with the Notch protein. It was confirmed that mutations in these loci will affect neurogenesis.<br />
|}<br />
<br />
===Overview of Molecular Mechanisms===<br />
Mammals possess a total of four ''Notch'' genes, with five genes for encoding the associated ligands, Delta-like and Jagged. The ''Notch'' genes each code for a single transmembrane receptor. Extracellularly, it contains epidermal growth factor (EGF)-like repeats for ligand interaction and Lin-12-Notch (LN) repeats for regulating the interactions between the extracellular and intracellular regions. Intracellularly, Notch has seven ankyrin (ANK) repeats and a transactivation domain (TAD), as well as a proline, glutamine, serine, threonine-rich (PEST) domain for degradation of Notch.<br />
<br><br><br />
[[File:Notch structure cartoon.jpg|thumb|700px|center|'''The structure of the Notch receptor.'''<ref name="PMID19255248"/> Extracellularly there are epidermal growth factor (EGF)-like repeats and Lin-12-Notch repeats (LNRs). The Notch intracellular domain (NICD) is made up of a rRBP-Jkappa-associated module (RAM) domain, ankyrin (ANK) repeats, and a proline, glutamine, serine, threonine-rich (PEST) domain. There are three sites for cleavage by enzymes: S1, S2, and S3/S4.]]<br />
<br />
====Canonical pathway====<br />
[[File:Overview of Notch signalling.png|thumb|500px|'''Summary of canonical Notch signalling.''' The interaction between Delta-like or Serrate ligands (DSL) and the Notch receptor on an adjacent cell initiates proteolytic cleavage of Notch and the release of the Notch intracellular domain (NICD). The NICD is then transported to the nucleus where it can induce transcription of Notch target genes by binding to specific proteins (MAM, CSL).<ref><pubmed>27404588</pubmed></ref>]]<br />
The canonical Notch pathway is unique in that it involves direct interaction between adjacent cells, as opposed to paracrine signalling, because both the Notch ligands and Notch receptors are transmembrane proteins found in the cell membrane. Furthermore, the lack of a secondary messenger or amplification process means that the Notch pathway has limited opportunities for regulation and must therefore be tightly controlled. Depending on its developmental and cellular context, activation or inhibition of the pathway can result in a variety of cellular responses, including cell death, proliferation, or differentiation.<ref name="Introduction to Notch Signalling">Yamamoto, S., Schulze, K.L. & Bellen, H.J. (2014). Introduction to Notch Signalling. ''Notch Signaling: Methods and Protocols''. Methods in Molecular Biology: 1187</ref><br />
<br><br><br />
Four Notch proteins are involved in the canonical pathway. NOTCH1 to NOTCH4 are single transmembrane receptors and can interact with a variety of ligands, including NOTCH ligands (e.g. Delta ligands) and Serrate ligands. There are three Delta ligands (Dll1, Dll3, and Dll4) and two Serrate ligands (Jagged1 and Jagged2) present in mammals.<ref name="Introduction to Notch Signalling"/> The binding between the Notch receptor and the ligand on the adjacent cell induces the release of the Notch intracellular domain (NICD) via a sequence of proteolytic reactions.<ref name="The Developing Human"/> Cell-cell interaction is therefore critical in the process of triggering Notch signalling.<br />
<br><br><br />
The interaction on the cell surface between Notch and its ligand on an adjacent cell causes the extracellular metalloprotease site (S2 site) to be exposed. The S2 site is then cleaved by transmembrane proteases belonging to the a disintegrin and metalloproteinase/tumour necrosis factor α converting enzyme (ADAM/TACE) family. The remaining Notch fragment subsequently undergoes two more intramembranous cleavages at the S3/S4 sites by the γ-secretase complex. Finally, the NICD is released and enters the nucleus to interact with CSL (CBF1, Suppressor of Hairless, Lag-1) and Mastermind-like proteins (MAMLs). CSL is a DNA-binding protein that acts as a transcription factor by forming repressor or activator complexes; in the absence of the NCID, CSL is bound to corepressor proteins (CoR) that prevent transcription of Notch target genes. MAMLs are transcriptional co-activators that are required for transcription of the target genes, hence they are involved in the regulation of the pathway.<ref name=PMID10075488/><ref name="Introduction to Notch Signalling"/> To stop signalling, the NICD is phosphorylated by kinases and ubiquitinated by E3 ubiquitin ligases, which results in proteasome mediated degradation and subsequent termination of the signal.<ref name="Introduction to Notch Signalling"/><br />
<br><br><br />
<br />
====Non-canonical pathway====<br />
Immense research has been carried out on the canonical Notch pathway and its members are well known. While canonical notch ligands control most of the known Notch signalling, a group of structurally distinct non-canonical ligands exist which activate Notch and its pleiotropic effects. Notch can non-canonically carry out its functions by post-translationally targeting Wnt/β-catenin signalling. This type of signalling is CSL-independent and can also work independently of ligands. Some genes are affected by the non-canonical Notch signalling, however their mediators in most cases are unknown. Notch binds and titrates levels of active β-catenin. Therefore, active β-catenin activity may serve as a useful readout for non-canonical Notch signals.<ref name="PMID22397947">As reviewed by <pubmed>22397947</pubmed></ref> <br />
<br />
Recent research has shown that Notch signalling plays crucial roles for cellular differentiation during development through γ-secretase-dependent intramembrane proteolysis followed by transcription of target genes. Hayashi et al. (2016) uncovered a ligand-dependent but γ-secretase-independent, non-canonical Notch signalling involved in presynaptic protein expression in postmitotic neurons.<ref name="PMID27040987"><pubmed>27040987</pubmed></ref><br />
<br><br><br />
<br />
====Transcriptional regulation of Notch signalling====<br />
A number of genes have been found to act as modulators of Notch signalling by modifying the ability of Notch to interact with its ligands. These include proteins acting extracellularly (Fringe, Brainiac, Egghead, Scabrous, Wingless), proteins acting at the cell membrane (Big brain), proteins acting intracellularly (Numb, Sanpodo, Disabled, Deltex, Dishevelled), and proteins acting within the nucleus (Hairless, EMB-5, Strawberry notch).<ref name="PMID9892565">As reviewed by <pubmed>9892565</pubmed></ref><br />
<br />
In ''Drosophila melanogaster'', it has been seen that ''fringe'' is able to affect the ability of Notch to be activated by the Serrate and Delta ligands. Specifically in the ''Drosophila'' wing, it was observed that Serrate did not interact with Notch in specific areas due to the action of ''fringe''<ref><pubmed>9247339</pubmed></ref>. Fringe is not required for initial Notch signalling, but is thought to be important for signalling processes when Notch activation occurs along the borders between distinct cell populations. Research suggests that Fringe specifically affects the binding between Notch and its ligands, rather than an activation step separate or subsequent to ligand binding. The ''brainiac'' and ''egghead'' genes are thought to either influence the production of a Notch ligand or act as substitute ligands themselves.<ref name="PMID9892565"/><br />
<br><br><br />
<br />
====Examples of Proteins Involved in Interaction with the Notch Intracellular Domain <small>(adapted from Table 3<ref name="PMID21828089"/>)</small>====<br />
{| class="pretty table"<br />
|-bgcolor="A3BFB1" <br />
| '''Protein'''<br />
| '''Interaction with NICD'''<br />
|-bgcolor="F5FFFA"<br />
| Adenamatous polyposis coli (Apc)<br />
| Controls Notch trafficking<br />
|-<br />
| Cyclin-dependant kinase 8 (CDK8)<br />
| Phosphorylates NICD to make it a substrate for ubiquitylation and degradation<br />
|-bgcolor="F5FFFA"<br />
| CBF1, Su(H) and LAG-1/Recombination signal binding protein for immunoglobulin kappa J region (CSL/RBP-J)<br />
| Main canonical transcriptional co-factor for NICD<br />
|-<br />
| Cyclin C (CycC)<br />
| Targets NICD for phosphorylation to make it a substrate for ubiquitylation and degradation<br />
|-bgcolor="F5FFFA"<br />
| Dishevelled (Dsh/Dvl)<br />
| Controls ligand-independent Notch trafficking; inhibits canonical Notch signalling<br />
|-<br />
| Deltex-1-4 (Dtx1-4)<br />
| Controls Notch ubiquitylation, processing, and internalisation<br />
|-bgcolor="F5FFFA"<br />
| Itchy, E3 ubiquitin protein ligase (Itch)<br />
| Promotes ubiquitylation of NICD<br />
|-<br />
| Mastermind-like 1/2 (Maml1/2)<br />
| Co-activator for NICD/CSL<br />
|-bgcolor="F5FFFA"<br />
| Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-ϰb)<br />
| NICD blocks NF-ϰb transcription of NF-ϰb target genes through binding to p50/cRel<br>NICD enhances NF-ϰb transcription of target genes by retaining NF-ϰb in the nucleus<br />
|-<br />
| Numb homolog (Numb)<br />
| Suppresses Notch signaling by recruiting E3 ubiquitin ligases to ubiquitylate Notch<br>Controls Notch trafficking during asymmetric cell division<br />
|-bgcolor="F5FFFA"<br />
| Smad family members (SMAD)<br />
| Smads enhance Notch signalling; Notch fine-tunes signalling through Smads<br />
|}<br />
<br><br />
<br />
===Roles in Embryonic Development===<br />
The phylogenetically conserved Notch signalling pathway plays a crucial role in the development of multiple organ systems, and is a major regulator of stem cell fate. It is responsible for the regulation of the transcription of a number of signalling molecules, such as ''MyoD'', ''Mash1'' and ''GATA2'', which are genes controlling the fate of myogenic, neurogenic and haematopoietic stem cells, respectively. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> The following subsections will further elucidate the vital roles of Notch signalling during normal embryonic development. If you would like to better understand human embryonic development before reading this section, [https://embryology.med.unsw.edu.au/embryology/index.php/Embryonic_Development| this page] serves as a great resource. <br />
<br><br><br />
<br />
====Cardiovascular====<br />
<br />
If you would like to generally learn about and become familiar with cardiac development in the embryo before reading this section, click [https://embryology.med.unsw.edu.au/embryology/index.php/ANAT2341_Lab_11_-_Heart here]!<br />
<br />
'''Cardiomyocyte Specification and Differentiation'''<br />
<br />
Expression during the appropriate window of the timeline of embryogenesis of Notch receptors, ligands and downstream effector molecules elucidates a role for the Notch pathway in the earliest stages of cardiac development. It has been found to restrict the expression of specific cardiogenic genes in a spatiotemporal manner and regulate cardiac field specification as early as during gastrulation. <ref name=PMID19580804><pubmed>19580804</pubmed></ref> Interestingly, Notch has been found to play both suppressive and promoting roles in cardiogenesis.<br />
<br />
For example, it has been shown that Notch suppresses cardiomyocyte cell fate specification during early cardiogenesis. This has been demonstrated through studies such as that carried out by Rones and colleagues (2000), which used activation and inhibition of Notch signaling in Xenopus. <ref name=PMID10934030><pubmed>10934030</pubmed></ref><br />
<br />
On the other hand, studies such as that by Boni et al. (2008) have found that Notch signalling may also promote myogenesis from cardiac progenitor cells. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> Cardiogenesis has also been promoted by downregulating Notch-1 activity in stem cells of embryos (Nemir et al., 2006).<ref name=PMID16690879><pubmed>16690879</pubmed></ref><br />
<br />
Despite the understanding that Notch signalling is crucial to embryonic myogenesis, the exact molecular mechanism remains elusive. Research by Buas and colleagues (2010) has explored such mechanisms by studying the Notch target, Hey1, which is known to suppress myogenic differentiation. They concluded that this inhibitory function of Hey1 is primarily mediated through binding near to myogenin and Mef2C promoters, which leads to cessation of target gene expression. <ref name=PMID19917614><pubmed>19917614</pubmed></ref><br />
<br />
[[File:Notch CVS simple diagram.png|thumb|500px|right|alt=Simplified Scheme of the Roles of Notch in Cardiac Development|'''Simplified Scheme of the Roles of Notch in Cardiac Development.''' Notch has been found to restrict the expression of specific cardiogenic genes in a spatiotemporal manner and regulate cardiac field specification early in development. Further after cardiac differentiation, Notch influences development of the AVC (atrioventricular canal), cardiac valves, ventricular trabeculae and the cardiac outflow tract. (This student-drawn image is based upon Figure 2 in the 2014 review by Zhou and Liu: [https://www.ncbi.nlm.nih.gov/pubmed/24345875 ''Role of Notch signaling in the mammalian heart.'']<ref name=PMID24345875><pubmed>24345875</pubmed></ref>)]]<br />
<br />
'''Development of the Atrioventricular Canal'''<br />
<br />
A study by Rutenberg et al. (2006) and another by Kokubo et al. (2007) implicate a role for Notch signaling in the region between the atria and the ventricles of the heart (the atrioventricular canal, or AVC).<ref name=PMID17021042><pubmed>17021042</pubmed></ref> <ref name=PMID17259303><pubmed>17259303</pubmed></ref> They used chicken and mouse models, respectively, to show that other signalling factors, ''Bmp2'' and ''Tbx2'', are restricted to the AVC region by Notch signalling during development. <br />
<br />
Furthermore, Watanabe and colleagues (2006) showed that deletion of Notch targets increases ''Bmp2'' expression and expansion of the AVC tissue, however other, non-Notch restrictive factors involved in AVC development are likely to exist.<ref name=PMID16554359><pubmed>16554359</pubmed></ref> <br />
<br />
'''Heart Valve Development'''<br />
<br />
In order for the heart valve to properly form in the embryo, endocardial to mesenchymal transformation (EMT) must occur. The Notch pathway, alongside Wnt and Bmp, has been found to regulate the process of EMT, defects in which can lead to congenital heart valve disease. Interestingly, Timmerman and colleagues (2004) demonstrated that this role of Notch may also promote oncogenic transformation. This team also showed that embryos exhibited abortive endocardial EMT if they were deficient in Notch signalling components in vivo and in vitro. <ref name=PMID14701881><pubmed>14701881</pubmed></ref> <br />
<br />
A more recent paper by Wang et al. (2013) further explored the underlying signalling processes and interrelationships of molecules that impact EMT. They found that Jagged1-Notch1 signalling in cells of the endocardium potentiates expression of Wnt4, which in turn carries out paracrine action on adjacent AVC tissue to upregulate Bmp2 expression and thus signal EMT. <ref name=PMID23560082><pubmed>23560082</pubmed></ref><br />
<br />
'''Trabeculation'''<br />
<br />
Trabeculation is the initial process of ventricular chamber development that forms a series of cardiomyocyte projections within the lumens of the ventricles of the heart (called trabeculae). Grego-Bessa and colleagues (2007) addressed the roles Notch plays in trabeculation through ''RBPJk'' (the gene product of which interacts with Notch) and ''Notch1'' gene manipulation. Mutants of these two genes showed perturbed expression and signalling of ''EphrinB2'', ''NRG1'' and ''BMP10'', alongside reduced proliferation of myocardiocytes. This research ultimately suggested that ''EphrinB2'' is a direct target of Notch in the endocardium that simultaneously requires the Notch-dependent action of BMP10 and NRG1 in order for ventricular myocardium proliferation and differentiation to occur normally. <ref name=PMID17336907><pubmed>17336907</pubmed></ref> Furthermore, the important process of trabeculation has recently been shown to be controlled by sequential Notch activation by an investigation by D’Amato et al. (2015). <ref name=PMID26641715><pubmed>26641715</pubmed></ref><br />
<br />
'''Development of the Outflow Tract'''<br />
<br />
About one third of congenital heart defects include malformations in the outflow tract which include the aorta, pulmonary arteries, aortic arch and ductus arteriosus. During cardiogenesis, neural crest cells interact with second heart field myocardium and endocardial mesenchyme. <ref><pubmed>20201902</pubmed></ref> <br />
Studies involving neurogenesis demonstrated the sensitivity of Notch signaling to temporal and spatial cues and showed the early Notch signaling initially controls the number of cells with a neurogenic fate and later dictates the lineage decision of neural versus glial cell fate. <ref><pubmed>16429119</pubmed></ref><br />
Neural crest precursors for ideal patterning of the outflow tract are required in the Notch signaling pathway. The use of a dominant negative form of a master mind like protein (MAML) which has shown to be a pan Notch inhibitor in neural crest cells inactivates Notch signaling. This results in congenital heart defects like pulmonary artery stenosis and aortic arch patterning defects associated with defects in smooth muscle formation. <ref><pubmed> 17273555 </pubmed></ref><br />
Part of the phenotype in defective neural crest cells is attributed to loss of Notch2 signalling as Notch2 inactivation in these cells produces small caliber aortas and pulmonary arteries because of defects in smooth muscle. <ref><pubmed> 18330927 </pubmed></ref><br />
Jagged1 is the ligand involved which signals to Notch on neural crest cell surfaces to induce vascular smooth muscle cell differentiation. <ref><pubmed> 18245384 </pubmed></ref><br />
Mutations in both JAGGED1 and NOTCH2 genes have been known to cause Alagille syndrome, further substantiating the importance of this pathway in proper formation of the outflow tract. <ref><pubmed> 16575836 </pubmed></ref><br />
<br />
Another study by Garg stresses the importance of Notch signaling in the outflow tract region. NOTCH1 mutations were seen in patients with aortic stenosis. Aortic stenosis results from the calcification of the aortic valve and is quite common in adults. However, in children, this may result in failure of the left ventricle to develop properly. NOTCH1 haploinsufficiency is also linked to early calcification and bicuspid aortic valve disease. This could be due to an early induction of Runx2 through the HRT genes.<br />
<ref><pubmed> 16025100 </pubmed></ref><br />
<br />
<br><br><br />
<br />
====Central Nervous System====<br />
<br />
If you would like to generally learn about and become familiar with neural development in the embryo before reading this section, click [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Neural_Development here]!<br />
<br />
[[File:Notch CNS simple diagram.png|thumb|450px|right|alt=Simplified Diagram of Roles of Notch in Neuronal Differentiation|'''Simplified Diagram of Roles of Notch in Neuronal Differentiation'''. Notch influences the differentiation of embryonic stem cells into neural cells via signalling with RBP (recombining binding protein), cyclin D1 and Hes1. (This student-drawn image is based upon Figure 1 from Chuang, Tung and Lin's 2015 review: [https://www.ncbi.nlm.nih.gov/pubmed/25815127 ''Neural differentiation from embryonic stem cells in vitro: An overview of the signaling pathways'']<ref name="PMID25815127"><pubmed>25815127</pubmed></ref>)]]<br />
'''Early Neural Differentiation'''<br />
<br />
Notch plays a major role in promoting neural commitment of cells. Lowell and colleagues (2011) used genetic manipulation to discover that the phenotype of stem cells is not affected by constitutively activated Notch in mouse embryonic stem cells (mESCs), however, interfering with Notch signalling -for example by pharmacological means- did impede neural fate determination. This role required Notch signalling via fibroblast growth factor (FGF) receptors. Furthermore, the conservation of the Notch signalling pathway within pluripotent stem cells is implied due to the existence of Notch ligands in stromal cells in human embryonic stem cells (hESCs) that induce neural differentiation. <ref name=PMID16594731><pubmed>16594731</pubmed></ref><br />
<br />
Das and colleagues (2010) manipulated Notch protein levels during specific stages of neural differentiation and found that if Notch signalling pathways were activated during day 3 of neural development for 6 hours, cell proliferation was dramatically enhanced. This was attributed to the induction by Notch of cyclin D1 expression. Without Notch signalling during neural development, there was reduced cyclin D1 levels. Manipulation of mESCs to express a dominant negative form of cyclin D1 resulted in abrogation of cell proliferation stimulated by Notch. Overall these results imply a temporally-specific role for Notch in CNS development, and that it requires cyclin D1 as a signalling molecule.<ref name=PMID20887720><pubmed>20887720</pubmed></ref><br />
<br />
Hes1 has also been shown to play a Notch-mediated role in neural progenitor maintenance, which is essential for proper development since cells need to proliferate only during specific periods in the embryo for the correct number, cell type and function to result. Shimojo, Ohtsuka and Kageyama (2008) used real time imaging in mice to show that Notch induces oscillatory expression of ''Hes1'' and other Notch target genes to maintain the complex temporal organisation of events in neural development. They concluded that further research could elucidate more about Hes1 oscillations in regards to neural progenitor maintenance, proliferation and differentiation <ref name=PMID18400163><pubmed>18400163</pubmed></ref>.<br />
<br />
Lastly, as well as influencing neural progenitor differentiation, it has been found that Notch also impacts the development and maintenance of polarised neural structures in the embryo. This was concluded from a knockout study in mice that elucidated a role for RBP (recombining binding protein), downstream of Notch, in modulating neural differentiation and maintaining rosette structure (an experimental ''in vitro'' correlate used for neural tube development) <ref name=PMID23675446><pubmed>23675446</pubmed></ref>. The researchers concluded that RBP knockouts lacked canonical Notch signalling and as a result showed multiple neurulation defects.<br />
<br><br><br />
<br />
====Other Systems====<br />
<br />
As aforementioned, Notch plays a wide array of roles in embryonic development, the follow table summarises these roles by each organ system:<br />
<br />
<big>Summary Table of Examples of Notch Signalling in Developmental Processes</big> <small>(adapted from Table 1<ref name="PMID21828089">As reviewed by <pubmed>21828089</pubmed></ref>)</small><br />
{| class="pretty table"<br />
|-bgcolor="CEDFF2"<br />
| '''Organ/Tissue'''<br />
| '''Processes regulated by Notch'''<br />
|-bgcolor="F5FAFF" <br />
| Brain<br />
| Controls the balance between gliogenesis and neurogenesis; stem cell maintenance<ref><pubmed>21262462</pubmed></ref><ref>As reviewed by <pubmed>20816397</pubmed></ref>; organisation and maintenance of polarity during early development<ref name="PMID23675446"/><br />
|-<br />
| Craniofacial structures<br />
| Palate morphogenesis: loss of Notch signalling results in cleft palate, fusion of the tongue with the palatal shelves, and other craniofacial defects; also involved in tooth development<br />
|-bgcolor="F5FAFF"<br />
| Ear<br />
| Defines the presumptive sensory epithelium; determines hair cell and supporting cell fates<br />
|-<br />
| Esophagus<br />
| Regulates esophageal epithelial homeostasis<br />
|-bgcolor="F5FAFF"<br />
| Heart<br />
| Cardiac patterning, cardiomyocyte differentiation, valve development, ventricular trabeculation, outflow tract development<br />
|-<br />
| Intestine<br />
| Controls proliferation and differentiation, including absorptive vs. secretory cell fates<br />
|-bgcolor="F5FAFF"<br />
| Limbs<br />
| Apical ectodermal ridge (AER) formation and digit morphogenesis, especially regulation of apoptosis<br />
|-<br />
| Lungs<br />
| Lateral inhibition between tracheal cells prevents extra cells from assuming the lead position during tracheal branching morphogenesis<br />
|-bgcolor="F5FAFF"<br />
| Neural crest<br />
| Controls patterning of neural crest precursors for the outflow tract region of the heart; regulates the transition from Schwann cell precursor to Schwann cell, controls Schwann cell proliferation and inhibits myelination; controls melanocyte stem cell maintenance<br />
|-<br />
| Pancreas<br />
| Specifies endocrine cell differentiation through lateral inhibition: endocrine lineage cells inhibit endocrine differentiation of their neighboring cells; maintains pancreatic endocrine precursor cells, inhibits terminal acinar cell differentiation; controls pancreatic epithelium branching and bud size<br />
|-bgcolor="F5FAFF"<br />
| Skin<br />
| Regulates cell adhesion, control of proliferation, hair follicle or feather papillae differentiation and homeostasis<br />
|-<br />
| Thyroid<br />
| Regulates the numbers of thyrocyte and C-cell progenitors and regulates differentiation and endocrine function of thyrocytes and C-cells<ref><pubmed>21364918</pubmed></ref><br />
|-bgcolor="F5FAFF"<br />
| Vasculature<br />
| Regulates arteriovenous specification and differentiation in endothelial cells and vascular smooth muscle cells; regulates blood vessel sprouting and branching<br />
|}<br />
<br />
====Quiz Your Notch-Knowledge on Embryonic Development!====<br />
<br />
<quiz display=simple><br />
<br />
{ In the development of which organ does Notch exert lateral inhibition to differentiate endocrine cells?<br />
|type="()"}<br />
- &nbsp; The heart<br />
- &nbsp; The central nervous system<br />
- &nbsp; The skin<br />
+ &nbsp; The pancreas<br />
|| Remember, Notch signals endocrine lineage cells of the developing pancreas to inhibit endocrine differentiation of their neighbouring cells, known as lateral inhibition. Notch plays various roles in the heart, central nervous system and skin, but not in this way. <br />
</quiz><br />
<br><br />
<br />
===Roles in Animal Development===<br />
The Notch signalling pathway doesn't just play a significant role in human development, but also affects events such as neurogenesis and myogenesis in some animals (thus why these animals are often used as models for human development in research!). Read below for information on some of these roles for Notch.<br />
<br><br><br />
<br />
[[File:Notch animals.png|thumb|450px|right|alt=Animals Whose Developmental Processes are Affected by Notch.|'''Animals Whose Developmental Processes are Affected by Notch.''' This is a simplified representation of a few examples of the animals (Drosophila flies<ref name=PMID21447553><pubmed>21447553</pubmed></ref>, C. elegans<ref name=PMID18599512><pubmed>18599512</pubmed></ref>, and the zebrafish<ref><pubmed>23840804</pubmed></ref>) in which development is influenced by the Notch signalling pathway, and their scientific names.]]<br />
<br />
====''Drosophila melanogaster''====<br />
<br />
'''(The Fly)'''<br />
<br />
Unlike the four Notch paralogs in humans, only one Notch homolog is present in ''Drosophila''.<ref name="Introduction to Notch Signalling"/><br />
<br />
Both canonical and non-canonical Notch signalling are involved in the structural and physiological responses and functional plasticity of olfactory receptor neurons in reaction to prolonged odour exposure.<ref><pubmed>26986723</pubmed></ref><ref><pubmed>26011623</pubmed></ref> Research has also shown that Notch is crucial for the formation of longitudinal connections in the Drosophila CNS. Kuzina, Song, and Giniger (2011) created temperature-sensitive mutations of Notch genes that prevented the development of mature longitudinal axon tracts. Additionally, it was found that the Notch phenotype appears at the earliest stages of the development of longitudinal connections in the CNS by observing early stage 13 embryos.<ref name=PMID21447553><pubmed>21447553</pubmed></ref><br />
<br><br><br />
<br />
====''Caenorhabditis elegans''====<br />
<br />
'''(The Worm)'''<br />
<br />
The Notch pathway in ''C. elegans'' occurs throughout development in populations of equipotent cells for neuronal function in postmitotic differentiated neurons. In these postmitotic neurons, there is a specialised post-embryonic development stage knows as 'dauer'. The Notch pathway is activated when cell signalling downstream of the developmental decision enter dauer. The Notch receptor glp-1 and the ligand lag-2 are expressed in the dauer stage and aid in maintaining this stage. Another Notch receptor, lin-12, functions upstream of insulin signalling components to promote conditions for growth and enhance dauer recovery. <ref name=PMID18599512><pubmed>18599512</pubmed></ref><br />
<br><br><br />
<br />
====''Danio rerio''====<br />
<br />
'''(The Zebrafish)'''<br />
<br />
The expression of Notch in the myogenic region and apical ectodermal ridge (AER) of the developing zebrafish fin is similar to what has been observed in developing chicken and mouse limbs, which shows how highly conserved the role of Notch signalling is in the development of appendages in vertebrates. During zebrafish embryogenesis, the timing and positioning of fin formation are dependent on Notch signalling. Notch is also involved in the actual processes of fin formation, such as AER signalling, chondrogenic differentiation, and myogenesis. In zebrafish embryos with defective Notch signalling, it was observed that the skeletal muscle fibres were thin and fragmented and the structure of the sarcomeres was significantly compromised. <ref name="PMID23840804"><pubmed>23840804</pubmed></ref><br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Expand this for an image from this research study</big><br />
|-<br />
|[[File:Abnormal pectoral fins are formed in Notch signalling disrupted larvae.jpg|thumb|450px|right|alt=Abnormal pectoral fins are formed in Notch signalling disrupted larvae|'''Abnormal pectoral fins are formed in Notch signalling disrupted larvae.''' (A–F) Live pictures of 5 dpf larvae. (A’) A pectoral fin from a sibling embryo showing the cartilaginous endoskeletal disc with individualized cells surrounded by thin matrix deposits, the fin fold and the chleitrum (n = 17) (E, E’). A similar pectoral fin was found in a DMSO-treated embryo (n = 9). Pectoral fins of Notch signalling disrupted embryos such as mibta52b (n = 18) (B, B’), jagged2 (n = 10) (C, C’) and Su(H)1+2 (n = 12) (D, D’) morphants and DAPT-treated embryos (n = 10) (F, F’) showing disorganized endoskeletal disc cells. cl, chleitrum; ed, endoskeletal disc; ff, fin fold.<ref name="PMID23840804"/>]]<br />
|}<br />
<br><br><br />
<br />
====Quiz Your Notch-Knowledge on Animal Development!====<br />
<br />
<quiz display=simple><br />
<br />
{In which animal (as described in this section) has it been shown that defective notch signalling leads to thinning and fragmentation of skeletal muscle fibres?<br />
|type="()"}<br />
- &nbsp; Drosophila melanogaster<br />
- &nbsp; I don't know!<br />
- &nbsp; Caenorhabditis elegans<br />
+ &nbsp; Danio rerio<br />
|| Remember, it was observed in one study that the skeletal muscle fibres of zebrafish (Danio rerio) were thin and fragmented and the structure of their sarcomeres were significantly compromised.<ref><pubmed>23840804</pubmed></ref> <br />
</quiz><br />
<br />
===Summary of Functions of Proteins Involved in Notch Signalling <small>(adapted from Table 1<ref name="PMID17761886"><pubmed>17761886</pubmed></ref>)</small>===<br />
{| class="pretty table"<br />
|-bgcolor="a3bfb1"<br />
| '''Mammals'''<br />
| '''''Drosophila'''''<br />
| '''''C.elegans'''''<br />
| '''Function'''<br />
|-bgcolor="F5FFFA" <br />
| Notch 1-4<br />
| Notch<br />
| Lin-12, Glp-1<br />
| Single transmembrane receptor and transcription factor<br />
|-<br />
| Delta 1, Delta3-4, Jagged1-2<br />
| Delta, Serrate<br />
| APX-1, LAG-2, ARG-1, DSL-1<br />
| Single transmembrane ligands of the Notch receptor<br />
|-bgcolor="F5FFFA" <br />
| CBF1/RBPJK<br>Mastermind1-3<br />
| Su(H)<br>Mastermind<br />
| Lag-1<br>Lag-3<br />
| DNA-binding transcription factor<br>Transcriptional co-activator<br />
|-<br />
| Lunatic, manic, and radical Fringe<br />
| Fringe<br />
|<br />
| Modifies both Notch and its ligands<br />
|-bgcolor="F5FFFA" <br />
| ADAM10, ADAM17<br />
| Kuzbanian, Kuzbanian-like, TACE<br />
| SUP-17, ADM-4<br />
| Metalloproteases targeting S2 Notch cleavage sites<br />
|-<br />
| Presenilin 1-2, nicastrin, APH1, PEN2<br />
| Presenilin, nicastrin, APH1, PEN2<br />
| SEL-12, APH-1, APH-2, PEN2<br />
| Proteins of the γ-secretase complex, which targets Notch S3 and S4 cleavage sites<br />
|-bgcolor="F5FFFA" <br />
| Mind bomb, skeletrophin, neuralized 1-2<br />
| Mind bomb 1-2, neuralized<br />
| Y47D3A.22<br />
| E3 ubiquitin-protein ligases that targets Delta and Jagged/Serrate and regulate their endocytosis<br />
|}<br />
<br><br />
<br />
===Abnormalities in Notch Signalling===<br />
Mutations in Notch genes and hence defects in Notch signalling have been implicated in the pathogenesis of several inherited diseases in humans.<ref name="PMID23729744">As reviewed by <pubmed>23729744</pubmed></ref><ref name="PMID22306179">As reviewed by <pubmed>22306179</pubmed></ref> The diseases listed in this summary table are only a few examples and are described in more detail below.<br />
<br><br />
<br />
{| class="pretty table"<br />
|-bgcolor="CEDFF2" <br />
| '''Disease'''<br />
| '''Gene'''<br />
| '''Phenotype'''<br />
|-bgcolor="F5FAFF" <br />
| Alagille syndrome ([http://omim.org/entry/118450 OMIM118450], [http://omim.org/entry/610205 OMIM610205])<br />
| ''JAG1'', ''NOTCH2''<br />
| Developmental abnormalities of the heart, liver, eye, and skeleton. Neonatal jaundice and cholestasis are early symptoms.<br />
|-<br />
| CADASIL ([http://omim.org/entry/125310 OMIM125310])<br />
| ''NOTCH3''<br />
| Autosomal vascular disorders linked to ischemic strokes, dementia, and premature death.<br />
|-bgcolor="F5FAFF"<br />
| T-cell acute lymphoblastic leukaemia ([http://omim.org/entry/613065 OMIM613065])<br />
| ''NOTCH1'' (mutation in heterodimerization domain or PEST domain)<br />
| Tumour derived from T-cell progenitors. Symptoms include anaemia and enlargement of lymph nodes in the liver and/or spleen.<br />
|-<br />
| Spondylocostal dysostosis ([http://omim.org/entry/122600 OMIM122600])<br />
| ''DLL3'', Lunatic fringe<br />
| Vertebral segmentation defects as well as rib abnormalities.<br />
|}<br />
<br />
====Alagille Syndrome====<br />
Alagille syndrome (AGS) is an autosomal dominant, multisystem disorder that mainly affects the liver, heart, and kidney. Diagnostic characteristics of the disease include liver disease, cardiac disease, vertebral defects, eye conditions, and facial features, as well as renal and vascular abnormalities.<ref>As reviewed by <pubmed>26548814</pubmed></ref> Two variants of AGS, type 1 and type 2, have been identified, and each is related to different defects in the Notch pathway. In clinically diagnosed cases of AGS type 1 (which accounts for approximately 97% of all cases of AGS), a mutation in the gene encoding the Notch ligand Jagged1 (Jag1) has been identified as a contributing factor.<ref>As reviewed by <pubmed>11745040</pubmed></ref> In the much rarer AGS type 2, a mutation in the NOTCH2 gene has been implicated in the manifestation of AGS. The mechanisms by which mutations in JAG1 and NOTCH2 lead to pathogenesis of AGS are not well understood, but it is known that normal Notch signalling is important in angiogenesis. Therefore, it is thought that abnormal JAG1 or NOTCH2 will cause disruptions to the pathway that leads to the vascular disorders present in AGS. This is also evidenced by research that JAG1 knockout mice suffer premature death due to vascular defects.<ref>As reviewed by <pubmed>21934706</pubmed></ref> It is possible that AGS caused by a mutation in NOTCH2 alone will lead to a different presentation than AGS patients with mutated JAG1; however, this is still undergoing further research. It is also unclear why AGS type 2 occurs at a significantly lower incidence than AGS type 1.<ref><pubmed>16773578</pubmed></ref><br />
<br><br><br />
<br />
====Spondylocostal Dysostosis====<br />
Spondylocostal Dysostosis (SD) is a collective term for conditions characterised by anomalies relating to rib and spine. The vertebrae are fused and shaped abnormally which can result in scoliosis. Similarly, the ribs may also be fused together or in some cases completely missing. As a result, people with this condition have short trunk dwarfism where their bodies are short in stature but have normal length limbs. Genetic changes are known to cause SD. SD Type 1 is the most prevalent form of this disease which is caused by the mutation in the delta like canonical Notch ligand 3 (DLL3 gene).<ref><pubmed>10742114</pubmed></ref> DLL3 provides the information for making a protein that regulates the Notch signalling pathway. The DLL3 protein in conjunction with the Notch pathway is primarily responsible for preventing the fusion of future vertebrae in a process known as somite segmentation.<ref><pubmed>11236715</pubmed></ref> An interruption in the Notch pathway inhibits the somite segmentation resulting in abnormalities relating to the ribs and spine as seen in SD. 25 percent of SD arise from mutations in the identified genes and further research suggest that other genes involved in the Notch signalling pathway may also be related to SD.<br />
<br><br><br />
<br />
====Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)====<br />
CADASIL is an autosomal-dominant disease of the small to medium-sized arteries, mainly in the brain, that leads to dementia and disability in mid-life. The symptoms, age of onset, and prognosis are variable. Distinguishing symptoms include subcortical ischemic events (60-80% of cases), cognitive impairment (60% of late stage disease), migraines (30-40%), mood disturbances (30%), and apathy (40%).<ref name="PMID21045164"><pubmed>21045164</pubmed></ref><ref name="PMID20301673"><pubmed>20301673</pubmed></ref> Approximately 5-10% of CADASIL patients also experience seizures. The mean age of onset is 45 years of age and the disease duration is between 10–40 years. More than 95% of CADASIL cases present with pathogenic mutations in NOTCH3 (located on chromosome 19p13), specifically the epidermal growth factor-like repeat domain.<ref name="PMID20301673"/><ref><pubmed>24579972</pubmed></ref> The NOTCH3 gene is involved in the normal development of blood vessels in both fetal and adult brains. In adults, NOTCH3 is expressed in the smooth muscle cells of arteries.<ref name="PMID21045164"/> There is currently no effective treatment available for CADASIL.<br />
<br><br><br />
<br />
====Congenital Heart Defects====<br />
<br />
'''Aortic Valve Disease'''<br />
<br />
[[File:Aortic valve disease.jpg|thumb|450px|right|alt=Loss of NOTCH1 expression in proximity to calcific nodules in human aortic valves|'''Loss of NOTCH1 expression in proximity to calcific nodules in human aortic valves.''' (A) Representative sections from control (A,B) and diseased (C-F) aortic valve cusps. (B) is high magnification image of boxed area in (A) and (D,E) are higher magnification of region in (C) while image in (F) shows another calcified aortic valve. Expression of Notch1 intracellular domain (NICD) is found in the thickened fibrosa of diseased aortic valve (C,E) as compared to the acellular fibrosa of control valves (A,B). However, there is significant loss of NICD expression in cells residing adjacent to calcific nodules (D,F). The fibrosa is oriented upward in all panels, and scale bars equal 100 microns (B,D,E,F are at same magnification). Brown signal represents NICD expression while nuclei are counterstained in blue.<ref name="PMID22110751"><pubmed>22110751</pubmed></ref>]]<br />
<br />
Calcification of the aortic valve is a leading cause of adult heart disease. Mutations in NOTCH1 have been found to cause various aortic valve abnormalities, including the development of a bicuspid aortic valve (as opposed to tricuspid) and valve calcification.<br />
<br />
&emsp;&emsp;A study by Garg et al. (2005) looked at mouse embryos and the expression of ''Notch1'' during development. It was found that during normal embryonic development, ''Notch1'' was abundantly expressed in the outflow tract mesenchyme (which develops into the heart valves) and the endocardium, as well as in the endothelial layer and mesenchyme of the aortic valve leaflets at the time of arterial trunk septation. Abnormal ''Notch1'' led to the death of mice from vascular endothelial defects. Garg et al. then investigated whether NOTCH1 was involved in calcium deposition and therefore valve calcification. This is thought to be due to differentiation of valve cells into osteoblast-like cells. This leads to the upregulation of osteopontin, osteocalcin, and other osteoblast-specific genes, which is normally regulated by the transcription factor Runx2. Runx2 is known to be upregulated in animal models of valve calcification. Garg et al. found that Notch1 was capable of repressing Runx2 activation. Heart tissue and vasculature are normally abundant with the hairy-related transcriptional repressors Hrt1 and Hrt2 (also called Hey1 and Hey2), which are normally activated by Notch and are key mediators of the Notch pathway. Hrt1 and Hrt2 were both expressed in the endothelium of the mice aortic valve leaflets, the endocardium, and the vascular endothelium. They were found to inhibit the activation of osteoblast-specific genes by Runx2. It was thought that Hrt proteins can repress Runx2 by physical interaction as well as mediate Notch1 repression of Runx2. Therefore, a defect in Notch will cause upregulation of Runx2, due to the lack of repressor activity by Notch itself and the activation of the repressors Hrt1 and Hrt2. This leads to the expression of osteoblast genes that results in the differentiation of valvular cells into osteoblast-like cells and ultimately causes aortic valve calficiation.<ref><pubmed>16025100</pubmed></ref><br />
<br />
The picture to the right is a histological image of aortic valve disease from a study performed in rats investigating molecular changes that occurred when Notch signalling was suppressed in the aortic valve.<ref name="PMID22110751"/><br />
<br><br><br />
<br />
====Tumourigenesis====<br />
Notch has been shown to be involved in cancer development and can act as both an oncogene and a tumour suppressor gene.<ref>As reviewed by <pubmed>14570040</pubmed></ref><ref name="PMID23729744"/> Defective Notch signalling has been implicated in the pathogenesis of several human cancers, such as acute myelogenous leukemia (overexpression of Jagged1 and Notch1), multiple myeloma (overexpression of Jagged1/2 and Notch1/2), and B-cell–derived Hodgkin lymphoma (overexpression of Jagged1 and Notch1).<ref name="PMID16291593">As reviewed by <pubmed>16291593</pubmed></ref><br />
<br />
Elevated levels of Notch ligand proteins and/or mRNA have been observed in several cancers. Upregulated Jagged1 mRNA has been seen in human pancreatic cancer; Jagged1 protein overexpression has also been studied in prostate, cervix, and brain cancers. Cervical cancers have shown upregulated Jagged2 mRNA. Additionally, elevated Dll1 mRNA has been observed in cervical cancers, as well as in human brain cancers at both Dll1 mRNA and protein levels. Additionally, defective Notch receptor expression has been implicated in cancer as well. For example, elevated Notch1 protein expression has been found in cervical, colon, lung, pancreas, skin, and brain cancers. Protein overexpression of Notch3 and Notch4 has also been seen in malignant melanoma and pancreatic cancer.<ref name="PMID16291593"/><br />
<br />
Interestingly, research has shown that Notch signalling can also have a tumour-suppressive effect. Studies have indicated that Notch signalling can inhibit proliferation and even stimulate apoptosis in malignant B-cells. Furthermore, the Notch1 intracellular domain has also shown the ability to induce growth arrest and apoptosis in Hodgkin lymphoma and multiple myeloma cells.<ref name="PMID16291593"/><br />
<br><br><br />
<br />
'''T-Cell Acute Lymphoblastic Leukaemia'''<br><br />
T-cell acute lymphoblastic leukaemia (T-ALL) is an example of how abnormal Notch signalling can lead to the development of cancer. T-ALL is an aggressive childhood cancer of the immune system's T-cells. The NOTCH1 gene encodes the Notch1 receptor, which is involved in the determination of pluripotent cell progenitors to T-cells and the organisation of these cells in the developing thymus. Activating mutations in the extracellular domain and/or the C-terminal PEST domain of Notch1 have been identified in more than half of all cases of T-ALL.<ref><pubmed>15472075</pubmed></ref><br />
<br><br><br />
<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! Other Examples of Roles of Notch in Cancer <small>(adapted from ''Notch in disease''<ref name="PMID23729744"/>)</small><br />
|-<br />
|-bgcolor="a3bfb1"<br />
| '''Gene'''<br />
| '''Role of Notch'''<br />
| '''Disease'''<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br>''NOTCH2''<br />
| Oncogene<br>Tumour suppressor<br />
| Pancreatic ductal adenocarcinoma<br />
|-<br />
| ''NCSTN''<br>''MAML1''<br>''APH1A''<br>''NOTCH2''<br />
| Tumour suppressor<br />
| Chronic myelomonocytic leukaemia<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br />
| Oncogene<br />
| Chronic lymphocytic leukaemia<br />
|-<br />
| Activated NOTCH<br />
| Tumour suppressor<br />
| Hepatocellular carcinoma<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br>''NOTCH2''<br>''NOTCH3''<br />
| Tumour suppressor<br />
| Head and neck squamous cell carcinoma<br />
|-<br />
| NOTCH<br />
| Tumour suppressor<br />
| B-cell acute lymphoblastic leukaemia<br />
|-bgcolor="F5FFFA" <br />
| ''NOTCH1''<br />
| Oncogene<br />
| Non-small-cell lung cancer<br />
|-<br />
| ''NOTCH1''<br />
| Oncogene<br />
| T-cell acute lymphoblastic leukaemia<br />
|}<br />
<br><br />
<br />
====Quiz Your Notch-Knowledge on Abnormalities in Notch Signalling!====<br />
<br />
<quiz display=simple><br />
{ What is the name for the collection of rib and spine abnormalities that result from interruption in the Notch pathway that leads to inhibition of somite segmentation in the embryo?<br />
|type="()"}<br />
- &nbsp; Alagille Syndrome<br />
- &nbsp; T-cell acute lymphoblastic leukaemia<br />
+ &nbsp; Spondylocostal Dysostosis<br />
- &nbsp; CADASIL<br />
|| Remember, Spondylocostal Dysostosis is a collective term for conditions characterised by anomalies relating to rib and spine. Genetic changes lead to an interruption in the Notch pathway that inhibits the somite segmentation resulting in abnormalities relating to the ribs and spine. Alagille syndrome is an autosomal dominant, multisystem disorder that mainly affects the liver, heart, and kidney. T-cell acute lymphoblastic leukaemia is an aggressive childhood cancer of the immune system's T-cells. CADASIL is an autosomal-dominant disease of the small to medium-sized arteries, mainly in the brain, that leads to dementia and disability in mid-life.<br />
</quiz><br />
<br />
===Current Areas of Research and Future Directions===<br />
Notch has been identified as having a role in the development of several cancers, and therefore research has recently begun investigating the use of Notch inhibitors in cancer treatment.<ref>As reviewed by <pubmed>27732970</pubmed></ref> γ-secretase inhibitors (GSIs), which inhibit the normal cleavage of Notch at the cell membrane and hence NICD release, have been a popular area of research. In the specific case of desmoid tumours, it was observed that treatment GSIs resulted in decreases in NICD and Hes1 expression in the tumour cells. Overall, tumour cell migration and invasion were decreased and cell growth was also inhibited.<ref><pubmed>26349011</pubmed></ref> GSIs have also been shown to have an inhibitory growth effect on pancreatic, breast, and lung cancers, but unfortunately they also produce side effects ''in vivo''.<ref>As reviewed by <pubmed>27688721</pubmed></ref> Therefore continued study into GSIs is required to make them safe for human treatment. Ultimately, with ongoing research, it is possible that the Notch pathway will eventually become an effective therapeutic target for cancers.<br />
<br><br><br />
<br />
<big><b>To search and read recent PubMed research and review articles on Notch, click <u>[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=Notch here]</u>!</b></big><br />
<br><br><br />
<br />
===Want to Read More About Notch?===<br />
The [http://www.omim.org/ OMIM (Online Mendelian Inheritance in Man) database] contains extensive information about the Notch genes and associated proteins and is a great place to go if you want to find out more about the Notch pathway in humans! Click on these links to learn more about the Notch genes that encode the human receptors and ligands:<br />
<li>[http://www.omim.org/entry/190198 NOTCH1] | [http://www.omim.org/entry/600275 NOTCH2] | [http://www.omim.org/entry/600276 NOTCH3] | [http://www.omim.org/entry/164951 NOTCH4]<br />
<li>[http://www.omim.org/entry/601920 JAG1] | [http://www.omim.org/entry/602570 JAG2]<br />
<li>[http://www.omim.org/entry/606582 DLL1] | [http://www.omim.org/entry/602768 DLL3] | [http://www.omim.org/entry/605185 DLL4]<br />
<br><br><br />
<br />
You can also look at these papers for examples of reviews and research papers that reinforce the diversity of how the Notch pathway functions in organisms.<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch influences adult development as well!</big><br />
|-<br />
|Interestingly, Notch does not only play a role in human embryonic development, but has also been found to influence developmental processes after birth. One of these processes is neurogenesis, for example.<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159580/ '''Not(ch) just development: Notch signalling in the adult brain.'''] <br />
<br />
This review explains that the Notch signalling pathway, which is so often regarded as a major molecular player in development, actually has important functions related to neural cells in the adult. As you would have read in the [[#Abnormalities in Notch signalling| Abnormalities in Notch Signalling]] section, Notch abnormalities are involved in a number of diseases, which underlines its importance in maintaining adult brain function. Some highlights of this review are: Figure 2 provides a schematic representation of precise roles Notch activation can play in the adult brain; explanations of the ways that Notch influences brain plasticity; and the discussion of conflicting results of studies exploring the role of Notch in stroke recovery.<ref name=PMID21505516><pubmed>21505516</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch Modulation for Therapy</big><br />
|-<br />
|As you would have read in the [[#Abnormalities in Notch signalling| Abnormalities in Notch Signalling]] section, Notch can play different roles in cancer development. An interesting review further elucidates that modulation of Notch signalling is actually being investigated as a potential target for cancer therapy:<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704338/ '''Targeting the Notch signaling pathway in cancer therapeutics'''] <br />
<br />
This articles focuses on reviewing data emerging from recent research, explaining how Notch contributes to the development of a number of cancers, and then outlining the current focuses of investigations into how to therapeutically manipulate the Notch pathway. Some highlights from this review are: the detailed description of how Notch interacts with other signalling pathways such as Wnt and the signalling cytokine Interleukin-6; explanations of the seemingly conflicting roles of Notch as a tumour promoter and suppressor; and discussion of the findings of various Notch-related studies in cancer stem cells.<ref name=PMID26767041><pubmed>26767041</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch influences reproduction in worker honey bees!</big><br />
|-<br />
| In our [[#Roles in Animal Development| Roles in Animal Development]] section we discussed Notch in relation to a number of animals, however one that we did not cover was the worker honey bee, or ''Apis mellifera''. A recent study shows that Notch also plays a role in these honeybees!<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976197/ '''Notch signalling mediates reproductive constraint in the adult worker honeybee.'''] <br />
<br />
This research paper essentially concludes that in the worker honeybee Notch signalling constrains reproduction between males and females; they were the first team to elucidate a molecular mechanism underlying the link between adult ovary activity in bees and the presence of the queen bee. Some highlights from this unique and interesting study are: the background explanation that female worker bees have suppressed activity due to pheromones produced by the queen; the finding that Notch plays a part in this inactivation of reproductivity; and the discussion about social control of reproduction and evolution.<ref name=PMID27485026><pubmed>27485026</pubmed></ref><br />
|}<br />
{| class="wikitable mw-collapsible mw-collapsed"<br />
! <big>Notch signalling is involved in embryo implantation!</big><br />
|-<br />
| Notch is essential for many developmental embryonic processes, as described in our [[#Roles in Embryonic Development|Roles in Embryonic Development]] section. Interestingly, research has shown that Notch signalling also has an important role in the initial process of establishing a successful pregnancy. Specifically, normal Notch signalling has been seen to be a critical factor in fetal-maternal communication during implantation and placentation. (To read more about these processes, go to these pages on [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Week_1_and_2_Development Weeks 1-2] and [https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Week_3_Development Week 3] of development.)<br><br><br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/24357662 '''Fetal-maternal communication: the role of Notch signalling in embryo implantation.''']<ref>As reviewed by <pubmed>24357662</pubmed></ref><br />
<br />
This review describes both human and animal studies of Notch signalling during pregnancy. It explains research of Notch signalling at the human blastocyst-maternal interface, and that Notch signalling has been observed in both the maternal endometrium and the blastocyst. Furthermore, Notch signalling is also important for the processes of implantation and placentation. Overall, the review summarises findings of Notch signalling in endometrial-trophectoderm interactions during the implantation, regulation of extravillous trophoblast invasion and spiral artery remodelling in the decidua, and angiogenesis in the placenta, as well as how abnormal Notch signalling is related with impaired placentation and pre-eclampsia.<br />
|}<br />
<br><br />
<br />
===Glossary===<br />
{| class="pretty table"<br />
|-<br />
| '''AER'''<br />
| 'Apical Ectodermal Ridge' is a structure that forms from the ectodermal cells at the distal end of each limb bud. The AER acts as a major signalling centre in order to ensure proper limb development.<br />
|-<br />
| '''Apoptosis'''<br />
| Programmed cell death which occurs in the development of many systems.<br />
|-<br />
| '''Calcification'''<br />
| The accumulation of calcium salts in body tissue. It normally occurs in the formation of bone, but abnormally calcium can be deposited in soft tissue causing it to harden.<br />
|-<br />
| '''Cardiogenic'''<br />
| From cardiogenesis - meaning formation of the heart.<br />
|-<br />
| '''Cardiomyocyte'''<br />
| The muscle cells (myocytes) that make up the cardiac muscle<br />
|-<br />
| '''Congenital'''<br />
| (Of a disease or physical abnormality) present from birth.<br />
|-<br />
| '''Craniofacial'''<br />
| Meaning relating to the cranium and the face.<br />
|-<br />
| '''Cyclin D1'''<br />
| A protein required for progression through the G1 phase of the cell cycle. Read more about it [https://en.wikipedia.org/wiki/Cyclin_D1 here], or see information on its encoding gene here: [http://omim.org/entry/168461 OMIM168461].<br />
|-<br />
| '''Endocardial'''<br />
| From endocardium - meaning the thin, smooth membrane which lines the inside of the chambers of the heart and forms the surface of the valves.<br />
|-<br />
| '''Endocrine'''<br />
| As in the endocrine system, refers to glands that secrete hormones or other substances directly into the blood.<br />
|-<br />
| '''Epithelium'''<br />
| The thin tissue that forms the outer layer of a body's surface and also lines the alimentary canal and other hollow structures.<br />
|-<br />
| '''Gastrulation'''<br />
| Describes the formative process of the formation of the trilaminar embryo containing the three germ layers.<br />
|-<br />
| '''Gliogenesis'''<br />
| The formation and development of glial cells (astrocytes, oligodendrocytes, Schwann cells, microglia).<br />
|-<br />
| '''Haematopoietic'''<br />
| From haematopoiesis - meaning the formation of blood cellular components<br />
|-<br />
| '''Haploinsufficiency'''<br />
| When a diploid organism has only a single functional copy of a gene (with the other copy inactivated by mutation), and so the total level of a gene product (a particular protein) produced by the cell is about half of the normal level.<br />
|-<br />
| '''Homeostasis'''<br />
| The ability to maintain a constant internal environment in response to environmental changes.<br />
|-<br />
| '''Ligand'''<br />
| A molecule that binds to a specific binding site on a protein (receptor).<br />
|-<br />
| '''Mef2C promoters'''<br />
| Myocyte-specific enhancer factor 2C is a transcription factor in the Mef2 family that is encoded by the gene ''MEF2C'' in humans ([https://omim.org/entry/600662 OMIM 600662]). This gene is involved in cardiac morphogenesis and myogenesis, as well as vascular development. It is thought to also possibly play a role in neurogenesis.<br />
|-<br />
| '''Mesenchymal'''<br />
| From mesenchyme - meaning a loosely organised, mainly mesodermal embryonic tissue which develops into connective and skeletal tissues, including blood and lymph.<br />
|-<br />
| '''Morphogenesis'''<br />
| Refers to the origin and development of morphological characteristics.<br />
|-<br />
| '''Myogenic'''<br />
| From myogenesis - meaning formation of muscle.<br />
|-<br />
| '''Myogenin'''<br />
| Also known as myogenic factor 4, this is a muscle-specific basic-helix-loop-helix transcription factor involved in the coordination of skeletal muscle development or myogenesis and repair.<br />
|-<br />
| '''Neural Crest'''<br />
| In vertebrate embryos, this is a transient structure that gives rise to most of the peripheral nervous system and to a number of non-neural cell types such as the smooth muscle cells of the cardiovascular system. <br />
|-<br />
| '''Neurogenic'''<br />
| From neurogenesis - meaning the formation of nervous tissue.<br />
|-<br />
| '''Neurulation'''<br />
| The folding process in vertebrate embryos whereby the neural plate transforms into the neural tube.<br />
|-<br />
| '''NICD'''<br />
| Notch intracellular domain<br />
|-<br />
| '''Oncogenic'''<br />
| From oncogenesis, also known as tumorigenesis or carcinogenesis - meaning the formation of a cancer, whereby normal cells are transformed into cancer cells.<br />
|-<br />
| '''Paracrine'''<br />
| A hormone that exerts an effect only in the vicinity of the gland secreting it.<br />
|-<br />
| '''Protease'''<br />
| An enzyme which breaks down proteins and peptides.<br />
|-<br />
| '''Runx2'''<br />
| Runt-related transcription factor 2 is a protein that in humans is encoded by the ''RUNX2'' gene ([http://omim.org/entry/600211 OMIM600211]). RUNX2 is an important transcription factor associated with osteoblast (bone substance-secreting cells) differentiation.<br />
|-<br />
| '''Stromal cells'''<br />
| The connective tissue cells of any organ. They support the function of the parenchymal cells of that organ. Fibroblasts and pericytes are among the most common types of stromal cells.<br />
|-<br />
|}<br />
<br />
====Further Glossary Links====<br />
[[A|A]] | [[B|B]] | [[C|C]] | [[D|D]] | [[E|E]] | [[F|F]] | [[G|G]] | [[H|H]] | [[I|I]] | [[J|J]] | [[K|K]] | [[L|L]] | [[M|M]] | [[N|N]] | [[O|O]] | [[P|P]] | [[Q|Q]] | [[R|R]] | [[S|S]] | [[T|T]] | [[U|U]] | [[V|V]] | [[W|W]] | [[X|X]] | [[Y|Y]] | [[Z|Z]] | [[Numbers|#]]<br />
<br />
===References===<br />
<references/></div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z5014803&diff=249826
User:Z5014803
2016-10-07T02:58:34Z
<p>Z5014803: /* Lab Attendance */</p>
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<div>{{ANAT2341Student2016}}<br />
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==Lab Attendance==<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 18:29, 5 August 2016 (AEST)<br />
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[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:40, 12 August 2016 (AEST)<br />
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[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:07, 19 August 2016 (AEST)<br />
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[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:09, 26 August 2016 (AEST)<br />
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[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:45, 2 September 2016 (AEST)<br />
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[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:13, 9 September 2016 (AEST)<br />
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[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:46, 23 September 2016 (AEST)<br />
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[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:58, 7 October 2016 (AEDT)<br />
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===Belbin Team Roles===<br />
In my previous courses, I was introduced to the Bebin model team roles as a way to identify myself in a team scenario. I definitely see myself as a "Shaper" since I am driven to try and complete the task at hand as soon as possible to ensure sufficient time for the editing process and the refining of the task. I also agree that I motivate other team members to progress through the task at a efficient pace such that the group does not lose momentum. I am also a person who is not afraid to speak my mind and thus will contest other viewpoints in order to spark a discussion. I identify myself as a very dynamic person in the way that I act according to the different predicaments I'm in and this results in numerous ways of efficiently solving any problems. Although I identify myself as a Shape I do not agree that i can become aggressive or bad humoured as I see some traits of a Co-ordinator in me. I have a very mature approach and recognise that each individual has a different way of attacking a problem and have learnt to appreciate others. <br />
<br />
===Lecture 1: Fertilisation===<br />
I have always been fond of the details surrounding fertilisation as it seems like a very interesting topic. It is more than just a sperm and egg cell coming together. The first lecture on fertilisation highlighted the various processes that need to occur in order to form a zygote, from gametogenesis to fertilisation and then forming the zygote. In my first year studies I learnt that there is a mechanism to prevent multiple sperm cells to enter the ovum but wasnt familiar with the process. The most interesting aspect of this lecture was precisely the process from fertilisation to the prevention of polyspermy. I was intrigued by how sperm cells are attracted to the oocyte which was through the ZP2 protein and only the nucleus of the spermatozoa enters the cell membranes. I was also interested in how membrane fusion will result in oocyte processes that will prevent polyspermy through the elevation of intracellular calcium levels. I had minimal knowledge of this topic but the lecture really made me want to learn about this process in a lot more detail.<br />
<br />
==New SubHeading==<br />
===External Link===<br />
[http://www.smh.com.au/ SMH]<br />
<br />
===Internal Link===<br />
[[ANAT2341 Lab 1]]<br />
<br />
[[ANAT2341 Lab 1|Fertilization Lab]]<br />
<br />
[[Student Page]]<br />
<br />
==Referencing==<br />
[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=fertilization fertilization]<br />
<br />
PMID 27486480<br />
<br />
==Assessment 1==<br />
<br />
<pubmed>27486266</pubmed> <br />
<br />
In order for fertilization to occur spermatozoa must be activated in a process known as 'sperm capacitation'. The primary research article "Seminal vesicle proteins SVS3 and SVS4 facilitate SVS2 effect on sperm capacitation" by Araki et al (2016) investigate the role of seminal vesicle secretion and how they inhibit the activation of spermatozoa and how they reduce the fertility of the capacitated spermatozoa (decapacitation). In previous studies it has already been shown that SVS2 acts as a capacitation inhibitor and a decapacitation factor and Araki et al (2016) build up on this pre existent knowledge about SVSs other than SVS2. The investigation utilised CD-1 mice, in particular female mice, to show the effects of SVS3 and SVS4 on sperm cells in the female reproductive tract. <br />
<br />
<br />
Levels of SVS3 and SVS4 were measured in each part of the female reproductive tract such as the copulaatory plug, vagina, oviduct and uterine region near the vagina and oviduct 1.5 hours post copulation. By using anti SVS3 antibody there were clear indications as to the specific roles of SVS3. Results showed that there were no SVS3 proteins in any of the aforementioned parts of the reproductive tract and thus the protein alone had no effects on sperm capacitation. In saying that, SVS3 proteins did show that they had the ability to potentiate the effects of SVS2. Similarly anti SVS4 antibody was utilised to provide insight into the function of this particular protein. Contrary to the findings for SVS3, SVS4 was detected in the uterus but not in any other part of the tract. This suggests that SVS4 has similar activity to that of SVS2 in a way that both the proteins enter the uterus. Thus, SVS4 acts as a capacitation inhibitor similar to SVS2 but results indicated that it does not have the decapacitation effect like SVS2.<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 18 August 2016 - You have added the citation correctly and written a good summary of this very recent article, still only available in the pre-published submitted format, findings. One thing, you must always include the full term in your summary (even if it appears in the paper title) before you begin to use the acronym. "SVS" (seminal vesicle protein secretion) could and may mean different things in different contexts.<br />
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| width=100px| Assessment 5/5<br />
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==Assessment 2==<br />
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[[File:Development_of_mouse_embryo_in_early_stages.png|400px|thumb|centre|Live imaging of the whole mouse embryo at E6 (A to D) and E5.5. (E to H)<ref><pubmed>23861733</pubmed></ref>]]<br />
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{| width=95%<br />
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| [mailto:m.hill@unsw.edu.au Mark Hill] 29 August 2016 - Reference and Copyright correctly included with the file and referenced on your page here. You have not included the <nowiki>{{Student Image}}</nowiki> template in the file summary box.<br />
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| Assessment 4.5/5<br />
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===References===<br />
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== Lab 3 Assessment ==<br />
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{| width=95%<br />
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| [mailto:m.hill@unsw.edu.au Mark Hill] 31 August 2016 - Lab 3 Assessment Quiz - [[Lecture_-_Mesoderm_Development|Mesoderm]] and [[Lecture_-_Ectoderm_Development|Ectoderm]] development. All correct, Well done!<br />
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| Assessment 5/5<br />
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==Assessment 4==<br />
==Quiz==<br />
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<quiz display=simple><br />
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{Which of the following structures does the ectoderm contribute to?<br />
|type="()"}<br />
- epithelium, mesentry, connective tissue<br />
+ enteric nervous system<br />
- epithelium and smooth muscle<br />
- enteric nervous system, connective tissue, smooth muscle<br />
|| Option two is correct as the ectoderm only contributes to the enteric nervous system. Epithelium is contributed by the endoderm, whereas the mesentry, connective tissues, smooth muscle, blood vessels are contributed by the mesoderm<br />
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{What lies rostral in relation to the notochord?<br />
|type="()"}<br />
- mesoderm<br />
- the neural tube<br />
+ the buccopharyngeal membrane<br />
- the mesoderm then endoderm<br />
|| The buccopharyngeal membrane lies rostral in relation to the notochord. The mesoderm lies laterally to the notochord, the neural tube dorsally and the mesoderm and endoderm ventrally.<br />
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{During Week 8- 10 (GA 10- 12 weeks):<br />
|type="()"}<br />
+ neural crest migrates into the wall forms enteric nervous system<br />
- endoderm in the GIT wall proliferates<br />
- a second rotation (of 90 degrees) occurs on the longitudinal axis establishing the adult orientation of the stomach.<br />
- mesoderm within the dorsal mesogastrium form a long strip of cells adjacent to the forming stomach above the developing pancreas<br />
|| Option A is correct and is the only one that occurs during weeks 8-10. Option B occurs at the beginning of Week 5. Option C occurs during Week 4. Option D also occurs in Week 5 and is incorrect<br />
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{Narrowing of a lumen such as the duodenum or the pylorus is also called:<br />
|type="()"}<br />
- duplication<br />
- atresia.<br />
+ stenosis<br />
- gastroschisis<br />
|| Stenosis is the correct answer. Duplication is the incomplete recanalization resulting in parallel lumens, this is really a specialized form of stenosis. Atresia is the interuption of the lumen and gastroschisis is a congenital abdominal wall defect which results in herniation of fetal abdominal viscera into the amniotic cavity.<br />
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</quiz><br />
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[[Student Page]]<br />
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==Lab 6 Assessment==<br />
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Completed ANAT2341 Lab 5 - Course Feedback Questionnaire<br />
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==Lab 6 Assessment==<br />
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===Identify a known genetic mutation that is associated with cleft lip or palate===<br />
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Tbx22 mutations are associated with cleft lip/palate<br />
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===Identify a recent research article on this gene===<br />
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[https://www.ncbi.nlm.nih.gov/pubmed/21375406 Arunee Kaewkhampa, D.D.S., M.S., Dhirawat Jotikasthira, D.D.S., M.S., Sutti Malaivijitnond, D.D.S., M.S.,<br />
Piranit Kantaputra, D.D.S., M.S '''TBX22 Mutation Associated With Cleft Lip/Palate, Hypodontia, and Limb Anomaly''' Cleft Palate Craniofacial Journal.: 2012, 49(2); 240-4 PubMed 21375406]<br />
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===How does this mutation affect developmental signalling in normal development===<br />
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==Lab 7 Assessment==<br />
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===Muscular Dystrophy===<br />
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'''''What is/are the dystrophin mutation(s)?'''''<br />
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The mutations in the dystrophin gene can sequentially lead to two types of muscular dystrophies; Duchene (DMD) and Becker (BMD) muscular dystrophy. DMD is the largest known gene in humans measuring 2.4Mb. The gene provides the coding for the a protein called dystrophin which is located primarily in muscles (skeletal and cardiac) and in minor quantities in nerve cells. In most cases mutations in this gene are of the deletion type in which pieces of DNA are lost. Other types of mutations include large duplications (pieces of DNA are copied) and point mutations (small changes in the DNA code). The aforementioned dystrophies arise from deletions in the dystrophin gene. <br />
<ref name="PMID23961084 "><pubmed>23961084</pubmed></ref><br />
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'''''What is the function of dystrophin?'''''<br />
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The dystrophin protein provides a structural link between the cytoskeleton of muscles and the extracellular matrix which attributes to maintaining the muscle integrity. It is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Although not much is known about the protein it is thought to cause membrane stabilisation and a lack of the protein can activate multiple pathophysiological processes. <br />
<ref name="PMID11917091"><pubmed>11917091</pubmed></ref><br />
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'''''What other tissues/organs are affected by this disorder?'''''<br />
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A gradual deterioration in lung function occurs as respiratory muscles weaken resulting in respiratory failure. The heart can also be affected in 1 of 2 ways namely abnormal heart rhythms and cardiomyopathy. <br />
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'''''What therapies exist for DMD?'''''<br />
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There is no cure for the disease as of yet but there are various research programs worldwide tackling this issue. There are also measures that can help manage the condition and improve quality of life. These include exercise, supportive environment, medical treatment (steroid treatment mostly), nutrition, surgeries, and palliative care. Other therapies that are currently under going research include gene therapy, reading through stop signals, stem cell therapy, utrophin upregulation, moosting muscle growth and reducing muscle damage<br />
<ref name="PMID22533379"><pubmed>22533379</pubmed></ref> <br />
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'''''What animal models are available for muscular dystrophy?'''''<br />
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The mouse is used animal model for muscular dystrophy. Other animal that have been utilised include the golden retriever dog and pigs. <br />
<ref name="PMID22137430"><pubmed>22137430</pubmed></ref><br />
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=<u>Lab 9 Peer Review</u>=<br />
<br><br />
<font size="4"><u>Group 1:</u></font><br />
<br><br />
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<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br><br />
Upon initially glancing over the project you can clearly see a range on headings and subheadings and it is evident by these that the project is about the WnT signalling pathway in skin of fetus. This is sufficient for assessment criteria 1 and 2 as you can see the aspect of research they are targeting such as skin formation during embryonic development. Throughout the text you can see citations relating to the topic and a range of references at the end of the project. This satisfies the requirements for criteria 3 but just a small critique would be to put these references in the references section just to clear out the unnecessary area. It can also be commended that the group project goes above and beyond the curriculum of informing us about the background information of WnT signalling pathway in skin of fetus but also includes the complications and diseases arising due to abnormalities in the WnT pathway. This is excellent and satisfies the requirements for criteria 5<br />
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There can be some improvements in the project but they are not necessarily of the utmost importance. Firstly, the group can add other specific subheadings and the relevant information under them such as the history or background of the signalling pathway. This is just so the reader has a more rounded knowledge of the pathway and can increase the interest and keep them engaged. It would also be good to see in the text and not just at the end of a paragraph. Such as, in the canonical and non canonical pathway heading it would be recommended to have in text citation and not just at the end just to show the reader where the information was gathered from.<br />
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<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
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Although the project has a fair amount of positives there are some areas that are lacking. Firstly, the report requires additional information in each section and how this information can be linked to pathways in embryological development. It would also be recommended to put in diagrams, images, tables etc. This would engage the reader and make the read more interesting since at the moment there are no images or tables. Also doing so will satisfy one aspect of criteria 2. This way the audience can develop a visual understanding of the topic. It would be advisable to put tables in the history section in the form of relevant dates/years and the information corresponding to the year. <br />
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Also, it would be good to see the role of WnT signalling pathway in something other than skin, for eg: an organ or tissue or cell. This would aid in achieving a higher mark for criteria 5 as you go above the required information. Overall it was great to see all group members contributing to the project but minor edits such as citations, images, tables, and adding additional information to sections would really captivate the reader and make it an enjoyable read. <br />
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<font size="4"><u>Group 3:</u></font><br />
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<b>Positive aspects of the project and suggested improvements: </b><br />
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The group project looks terrific at the initial glance. You can clearly see all the headings and subheadings. In particular, it is great to see a range of subheadings such as “limb bud formation”, “bone development”, “kidney development”. This shows that there was a lot of research put into this project. Also by doing so you have made it clear that your project is about the Fibroblast Growth Factor Receptor Pathway (FGFR). The page is also very easy to navigate as well which was nice to see. <br />
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It is also great to see that there is addition of tables, images, and diagrams as it kept the read a lot more interesting and captivating. This allowed you to successfully satisfy criteria 2. It is also good to see correct in text citations and references as this allowed the reader to search for additional information if interested or necessary. Although you haven’t made up any multiple choice questions it is excellent to see a MCQ section. This is a great way to test the readers’ knowledge and in turn you can reflect if you have provided accurate and sufficient information to answer these questions. <br />
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It was great to see that you added an abnormalities section and in particular different types of syndromes and disorders. This meant that you went over the minimum information required and put in extra effort to create a coherent project. This satisfied criteria 5 and thus a better project. Overall there are many positives in this report and with minor amendments such as adding information to sections such as “Apert syndrome”, “Animal models”, “Kidney development”, “external genitalia development” etc, a very articulate and well rounded project will be created.<br />
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<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
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Although there are many positives in the project, there should be some amendments to the project just to ensure all bases are covered. Firstly, it would be advised to increase the amount of information to the introduction and history sections. As these sections are lacking information, the reader may not have enough information to carry on reading as their base on this topic isn’t really strong and lacks information. This can easily turn off new readers and inhibit further exploration of the topic/ project. By adding additional dates in the history section, a better overall knowledge and background of the signalling pathway can be developed which can only enhance learning. <br />
<br><br />
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Overall, there are not many negatives and I believe as a reader your project was a great example of progress so far and with the aforementioned minor tweaks, your group is well on their way to achieving extremely high marks. <br />
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<font size="4"><u>Group 4:</u></font><br />
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<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
At initial glance I can see a range of headings and subheadings which just made it easier to navigate from one aspect of the project to another. This satisfied the requirements for criteria 1 and 2. This also allowed me to recognise the main topic of the project is the Hedgehog signalling pathway. There is also an addition of an image of the pathway which was great to see as it outlines the main components of the pathway and in general educates the reader about the signalling pathway. This provided a visual stimulus/ description which in turn engaged the reader to find out more about the topic.<br />
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It was also good to see correct in text citations and a references list at the end which in turn satisfied criteria 3. To satisfy criteria 5 it was excellent to see information that was well beyond the required information. An example of this is when discussing the role of the pathway in not only humans but also in mice, chicks and fruit flies. The group also began to include new research and abnormalities related to the Shh pathway which aided in rounding off criteria 1. <br />
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In order to improve the already positives of this project it would be advised to add a description to the image just so the reader can have some sort of summary about the main points of the image/ pathway. Also, addition of diagrams or tables in some of the subheadings would be good as it will keep the reader interested and in general provide a visual aid. Also it is necessary to cite and provide a reference of the image as it breaches the copyright laws. <br />
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<b>Negative aspects of the project and suggested improvements: </b><br />
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Although there are positives to the project, there are a few negatives that can easily be fixed. It is crucial to put in an “Introduction” heading and providing relevant information. This in turn will create a coherent project as it flows from one aspect to another whilst simultaneously providing a brief overview of the Sonic Hedgehog Pathway. Although you have explored the mechanism in animal models it is imperative to link this to embryological development. Also, addition of diagrams, interactive quizzes and tables is necessary to satisfy criteria 3, since 1 image is not enough. <br />
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Adding a glossary of terms at the end of the project is needed to clarify any words or phrases that have not been previously encountered such as “organogenesis”, “paracrine”, “dephosphorylation” etc. Overall, the project is coming along nicely and with the recommended amendments, a high mark is definitely in order. <br />
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<font size="4"><u>Group 5: </u></font><br />
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<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br />
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Upon reviewing the page, it is evident that there has been a lot of research put in this project. Initially, there is evidence of a range of headings and subheadings which allowed the navigation from one aspect of the project to another extremely easy. This allowed me to confirm that the project is about T-box genes and their signalling. Secondly, it was excellent to see a range of images, tables and graphs as they provided visual aids to learn more about the topic and in general made it easier to accumulate information. Also it was good to see that these tables and images were correctly cited and referenced at the end which meant that there was no breach of copyright laws. <br />
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Also, throughout the project there was sufficient amount of information in each subheading which meant that the reader gained all relevant information pertaining to the section that they are reading. It was also great to see a range of abnormalities being added to the project. This meant that you have went above and beyond the scope of the assessment and researched that extra bit to provide additional information about the signalling pathway and complications arising from any mutations. This meant that you successfully satisfied criteria 5 and thus a more rounded project. <br />
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<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
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This project certainly contains a range of positives but there were minimal negatives that can easily be amended in order to achieve a very high mark. I noticed that there was more than 1 image being used from Wikipedia and the criterion clearly says that a maximum of 1 was allowed. This is not a big deal but just in case there is harsh marking and penalties, it is advised to replace the additional image with another image. In addition, it would be useful to add a glossary of all the terms that one may find confusing such as “homologues”, “heterozygous”, “homology”, “notochord” etc. This in turn will provide the reader with enough information to understand the context of the project and in turn keep them engaged.<br />
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Another negative aspect of the project was that the subheading “Ancient origins and evolution of the T-box gene family” randomly appearing nearing the end of the project. This looked a bit out of place and not flowing with the rest of the passage. To correct this it would be advised to add this to the start of the page with the “Origin of the T-box genes” section just so the information clearly flows from one topic to another without creating confusion. Overall, this project is coming along quite nicely. It is evident that a lot of research has been put into constructing a coherent and succinct project but also have the visual cues to back up the main aspects. To maximise marks, it is recommended to reflect on the feedback and correct the minor mistakes. <br />
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<font size="4"><u>Group 6:</u></font><br />
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<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Upon reviewing the page I can see a number of headings and subheadings such as the nature of the growth factor, its mechanism of action, history and emerging research. But to be critical, a range of other headings is necessary to ensure all bases are covered when researching and providing the relevant information. This will help in satisfying the requirements for criteria 1 and 2. It is good to see the addition of a diagram to your project as it is a requirement for criteria 2. This provided a visual aid that kept me interested to find out more about the topic while simultaneously making it easier to understand the theory behind the process of TGF Beta signalling pathway. It is also great to see the current research and limitations as this shows that you are going beyond the scope of the required criteria and researching ahead to provide that extra bit of information. This in turn is a great way to satisfy criteria 5.<br />
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<br><br />
<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Although there are a few positives in the project, there are a number of negatives which can be improved upon to ensure a coherent project is created. Firstly, it is advised to put the heading “history of TGF- beta signalling pathway at the top” with the introduction as this is an introductory section and should be addressed initially on the page. This will allow you to create a more flowing page which also looks nice. Secondly, it would be advised to add more images and tables as it is a requirement for criteria 2. By doing this you will keep the reader engaged and wanting to find out more about the chosen topic. In saying that, you already have a couple of images but not referenced. It is imperative to correctly cite and reference these images as failure to do so will result in a breach of copyright laws. <br />
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Another critique is to add more subheadings with a range of different aspects of the signalling pathway being explored. It is recommended that you dedicate a chunk of your project to describing the pathway in detail and its role in embryonic development and abnormalities relating to mutations caused by the pathway. This will ensure you answer criteria 6 as it is a great deal of the report. It is also advised to put the history section under the introduction section as placing it in the middle of the project is a bit out of place and inhibits the flow of the information from one subheading to another. Also, the history section can be improved by adding more information as there have been more findings in this research topic since the 1970s. An addition of glossary is also needed for terms such as “peptide”, “cytokine”, “angiogenesis”, “protein kinase” etc. This will aid readers understand terms that they previously have not encountered and allow them to correctly understand the context of the information. <br />
<br><br />
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It has also come to my attention that there are little to no references or in text citations. By adding information without correctly giving the authors credit is a breach of copyright laws and must be done urgently. Overall, the project shows signs of progress with a number of positives. By reflecting on the negative aspects and acting upon it, it is certain that high marks are in order.</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2016_Group_Project_1&diff=249634
Talk:2016 Group Project 1
2016-10-06T16:40:11Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016discussionheader}}<br />
=Peer Review=<br />
<font size="4"><u>Group 1:</u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br><br />
Upon assessment of this project, it appears that the authors have devised a variety of subheadings related to the signalling pathway of the Wnt receptor in embryonic development which is excellent. The group has also began investigating the involvement of Wnt in numerous aspects of embryonic development such as skin formation. The use of subheadings and headings related to the Wnt receptor partially meets criteria 1 and 2 assessment. It also appears that the group has cited and referenced sources for some of the information utilised, particularly when describing the “Caronical Pathway”. This also partially meets criteria 3 for this assessment. The group has also attempted to explore abnormalities in the Wnt pathway by describing interruptions in the pathway and its relation to cancer which is very interesting. They have therefore attempted to research ideas related to this receptor that extend beyond formal teaching activities, by explaining the link between Wnt abnormalities and disease (criteria 5). <br />
<br><br />
<br><br />
Whilst there are the positive aspects of the page, improvements can still be made to ensure that the group satisfies the first five points of the marking criteria. Firstly, although there appears to be subheadings, there only appear to be few and therefore it would be excellent to add more subheadings. Subheadings may relate to the history of the Wnt signalling pathway or even subtypes of the receptor as well as their respective functions. In addition, whilst the group appear to have cited some of their sources, it is important to cite all sources, particularly when gathering data under the “Non-canonical pathway” subheading. Although a series of articles have been referred to, it is vital that the group includes in-text citations in order for the audience to determine the source for each segment of information. A suggestion would be to investigate more examples of diseases caused by abnormalities in the Wnt signalling pathway<br />
<br><br />
<br><br />
<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
The group appeared to provide a general description of the abnormalities associated with disruption of the Wnt pathway; however they did not talk about abnormalities in the context of embryonic development. A suggestion would be to discuss Wnt abnormalities to the effect it has on embryonic development. It was also noticed that the group failed to include diagrams, tables or figures to reinforce the information. The use of diagrams would assist the audience in developing a visual understanding of the information presented and also makes the wiki page more appealing too. Therefore, a suggestion would be to use diagrams and figures. For example, a diagram of the signalling pathway would be a suggestion. It was noticed that the page appears to have no introduction or history describing the Wnt receptor. Therefore, a possible improvement would be to include a brief introduction and history at the beginning of the page as well as a few diagrams to provide the audience with an insight into what the receptor’s purpose is before exploring its function in embryonic developing.<br />
<br><br />
<br><br />
In addition, it appears that the group has focused on the role of Wnt in skin development of the embryo only. A possible improvement would be to investigate the involvement of Wnt in other areas of embryonic development, perhaps the development of specific organ systems or other structures.<br />
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<br><br />
<br><br />
<br><br />
<br><br />
<br><br />
To all group members:<br />
*More info on pathway focusing on fetus development, and which pathway it is majorly part of - focus research on those body parts<br />
*Make your section presentable<br />
*At least one picture per section<br />
<br />
===Group 1===<br />
<br />
You guys have made significant progress on your project, managing to touch briefly on each section of your assignment. There have been some good choices of subheadings but I think some improvement can be made. For example, I think it would be useful to breakdown the general heading of ‘introduction’ into smaller subheadings so readers are made aware of what will be discussed in this section. It would also be useful to touch upon the importance of this pathway and thus, highlighting its significance in embryological development. <br />
<br />
In terms of the content of the project, being only in the draft stage a considerable amount of editing is required. For example, there has been mention of the TCF/LEF family and though the use of this abbreviations is useful, I think it would be appropriate to initially include the full name and explain this term in brief detail. In addition, there has been discussion of the ‘canonical’ and ‘non-canonical’ pathways of WnT Signalling Pathway but you could consider discussing the significance of having these two separate pathways. Comparing and contrasting these two pathways may also assist in aiding one’s understanding of the topic. <br />
<br />
Though it is great that you have made progress, I think more detail is required in each section, particularly in linking the effect of these pathways on embryological development. Also, greater attention needs to paid to referencing and utilisation of studies that have dissected this signalling pathway. For example, greater emphasis can be placed on studies performed on ‘embryos of Xenopus laevis’ or the in vitro experiments on mice. Instead of saying ‘a study’ or ‘another study’ acknowledge the researchers of this study as it will increase the validity of your argument while providing readers with the opportunity to refer back to these papers for more information if required or interested. More detail is also required on the effect of this pathway on skin formation. One way this could be done is by expanding on the information already provided, for example, explain how ‘WnT signalling inhibits the ectoderm’s responsiveness to FGFs’ and provide a detailed explanation of the feedback mechanism. Though your topic is focusing on ‘WnT Signalling pathway in the skin of fetus’ It would be beneficial to explore the roles of Wnt signalling in other areas of embryological development as this could provide insight into the abnormalities caused by mutations in this pathway. In terms of the ‘what can go wrong’ section, try breaking this segment into the various embryological deficiencies that can develop through disruption of the WnT pathway and try and make it relevant by providing statistics. <br />
<br />
Overall, you guys have done a fantastic job! It was good to see that all group members had contributed to the project. The main thing that requires improvement is the lack of detail. Through editing and inclusion of appropriate references and citations you can significantly improve the quality of your work. It would be useful to add some diagrams or images to help explain the pathway. In addition, try utilising your discussion page and communicating with your other team members. By providing feedback and suggestions you can assist in efficiently producing an excellent project. I hope this helps!! <br />
<br />
===Group 1 Critical Assessment===<br />
In terms of the topic of WnT signalling pathway, the page is beginning to come together with a great amount of information. What I particularly like is how the different concepts introduced in the page have been explained, for e.g. the different WnT pathways. However the content for each pathway does not seem to be consistent. While the canonical pathway addresses the mechanism, the non-canonical one doesn’t. I would suggest constructing a table to compare the similarities and differences between the various pathways, and adding images or shorts clips with audio to represent the elements of the pathways in a different form. This would not only enhance the look of your page but also make it more interactive for the audience. <br />
<br />
A great positive is to see links to research articles have been provided for the audience to access if they are interested to read on further. The links are short and easy to see, and direct you straight to the article on Pubmed, a reliable source. An effort has also been made to summarise the article, however the summary should be available as a simple breakdown so the audience can refer to it if they struggle to understand. The summaries include some jargon that can be further simplified. <br />
<br />
In relation to criteria 1, the key points have definitely been highlighted and the signalling pathway has been associated with the fetal development, however to make it more interesting and satisfy criteria 5, possibly construct a table or briefly outline how WnT signalling is involved in other areas such as Type 2 Diabetes and Cancer. Furthermore, to relate the topic back to embryological development explore the pathway in other areas such as gastrulation, rather than limiting discussion to skin development.<br />
<br />
Lastly to satisfy criteria 3, attempt to include in text citations within the paragraphs, instead of displaying references towards the end of the page. Overall, great job in gathering and highlighting key features, and backing up your information with relevant articles!<br />
<br />
===Group 1 Peer Assessment===<br />
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The start you have made on your project appears to be quite decent. There seems to be a clear overview and scaffold of how your page will look and what it will discuss in the end. For the most part the usage of dot points has made understanding your points with regards to the signaling pathways (Canonical pathway section) a lot easier as opposed to having a wall of text. I would recommend possibly adopting dot points when explaining the pathway regarding the Wnt-Calcium Ion pathway to make it easier to digest. That being said though, there are areas within your wiki page that would most likely benefit from having complete paragraphs such as your sub sections labeled under the non-canonical pathway. It appears that each individual point in the sub section role appears to represent individual points that could be substantially elaborated on. In way I feel that it would make the ideas in the section less disjoint and more clear, given that writing in a paragraph format would be suitable for longer passages. Also for the part where there are there are research articles linked, and descriptions of such articles, it might be better to try integrate such ideas into other main components of your wiki page, because they seem quite out of context and out of nowhere. That being said you could also just put this under a current research heading and talk about it with respect to the current findings of the Wnt pathway. <br />
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Another main aspect that should be corrected is that in some sections, there is the assumption in your wiki page that the reader fully understands all your abbreviations. I know it sounds silly but it is probably best that your group coordinates or finds where you first use an abbreviation such as CaMKII in your non canonical pathway section and change it to the unabbreviated name, with the abbreviated name in brackets, where from there you can just use the abbreviated name. Also maybe just providing a glossary of the abbreviated terms and their unabbreviated terms at the end of your page will do as well. Also its good to keep in mind that you may have already done this for some terms, so look out for that as well.<br />
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With regards to your referencing, I see that it is quite extensive, but there seems to be a lack of in text citations. As a result, its quite hard for those who read your page to quickly find the appropriate citation with regards to the sentences or dot point being read. For the sections such as “Canonical Pathway: How it works” this isn’t too bad, as there is only one reference, but for the “Non-Canonical Pathway section” there are way too many for it to be easy to tell where the citations are associated to. So overall for this I recommend your group to use in-text citations. Also I’ve noticed that you have used a review to cite your whole “Canonical pathway: How it works” section, which for the most part most likely contains all your information you have stated, but doesn’t give credit to the specific or individual authors included in the review and also requires the reader to go and find the specific sections in the review that you have used to cite your text. It is such that it would be better to use research articles to site your individual points, maybe extracting such research articles from the review article itself. <br />
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Overall the start made on your project is appearing to take shape, where I see that there are many subheadings yet to be filled below the “Wnt-Calcium Ion pathway” section. I’m sure if your groups keep up the quality of the work, your page should turn out fine with the addition of incorporating the feedback I have provided. <br />
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===Group 1 – Wnt Signalling Pathway===<br />
Positive aspects of the project include that fact that this group has included detailed information of the different WnT signaling pathways. It does seem however, that this information would perhaps be better conveyed to the audience if it were accompanied with images (either sourced from the internet or hand drawn) and/or videos/animations, as well as some information on the role of each signaling molecule/receptor subtype (perhaps in a table) just to provide a more thorough explanation of this pathway. Furthermore, this group has made a conscious decision to include a glossary, although they have not yet started this, it is going to be something the group can add to whilst finishing the project and will help the reader better understand the concepts they discuss. This group has included a large amount of references throughout their project, including a significant amount of recent primary articles, which shows the reader that their information is well researched and very current. However, the only criticism here is that they aren't appropriately formatted for the purpose of this assignment. I would suggest that in text citations would be more appropriate, so the reader can clearly identify where this specific information is from and then go directly to said source if need be. <br />
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Alternatively negative aspects of the project, which may need some revising before submitting the final version of this assignment, would be the formatting of the project as it appears relatively incomplete. Although there are some subheadings, which are helpful, it may be useful to add additional ones to these to make it a little clear for the reader. For example perhaps use a similar scaffold to the other group projects, which have included ones such as introduction, history, outline of the signaling pathway, its specific roles in embryonic development and then abnormalities specifically relating to embryonic development, as this would help break up the information better and make the projects more consistent for readers. Most of the work on this project seems to focus on explaining the signaling pathway so I assume its more the case of the group hasn’t got around to it yet, but I think more information on the role this signaling pathway specifically has in embryonic development is required, like the paragraph on early stages of skin formation, in order to tie in the assignment with what we have been learning in the labs and lectures. As mentioned I think the subheadings may need some revision, and the current ‘What can go wrong’ may be better described as ‘abnormalities’ that way you could also include a discussion of abnormalities to Wnt that specifically influence normal embryonic development, as well as still include the paragraphs on its influence on tumor cells which could perhaps be found using the ‘omim’ site searching by a receptor subtype or pathway. Also, although you have included more of a discussion of abnormalities that occur later in development, it is interesting for the reader and does go beyond our understanding from class, but the main focus probably should be on abnormalities in embryonic development. <br />
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In conclusion this project is definitely on its way to being really good, the information on the signaling pathways appears to be well research. The major criticisms were mostly focused on presentational aspects of the project like subheadings, references and the inclusion of images/tables. With some more research on its role in early embryonic development and abnormalities this will be very successful. <br />
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===Group 1 Peer Assessment===<br />
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Positive aspects of the project and improvements:<br />
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Upon initially glancing over the project you can clearly see a range on headings and subheadings and it is evident by these that the project is about the WnT signalling pathway in skin of fetus. This is sufficient for assessment criteria 1 and 2 as you can see the aspect of research they are targeting such as skin formation during embryonic development. Throughout the text you can see citations relating to the topic and a range of references at the end of the project. This satisfies the requirements for criteria 3 but just a small critique would be to put these references in the references section just to clear out the unnecessary area. It can also be commended that the group project goes above and beyond the curriculum of informing us about the background information of WnT signalling pathway in skin of fetus but also includes the complications and diseases arising due to abnormalities in the WnT pathway. This is excellent and satisfies the requirements for criteria 5<br />
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There can be some improvements in the project but they are not necessarily of the utmost importance. Firstly, the group can add other specific subheadings and the relevant information under them such as the history or background of the signalling pathway. This is just so the reader has a more rounded knowledge of the pathway and can increase the interest and keep them engaged. It would also be good to see in the text and not just at the end of a paragraph. Such as, in the canonical and non canonical pathway heading it would be recommended to have in text citation and not just at the end just to show the reader where the information was gathered from.<br />
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Negative aspects of the project and improvements:<br />
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Although the project has a fair amount of positives there are some areas that are lacking. Firstly, the report requires additional information in each section and how this information can be linked to pathways in embryological development. It would also be recommended to put in diagrams, images, tables etc. This would engage the reader and make the read more interesting since at the moment there are no images or tables. Also doing so will satisfy one aspect of criteria 2. This way the audience can develop a visual understanding of the topic. It would be advisable to put tables in the history section in the form of relevant dates/years and the information corresponding to the year. <br />
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Also, it would be good to see the role of WnT signalling pathway in something other than skin, for eg: an organ or tissue or cell. This would aid in achieving a higher mark for criteria 5 as you go above the required information. Overall it was great to see all group members contributing to the project but minor edits such as citations, images, tables, and adding additional information to sections would really captivate the reader and make it an enjoyable read. <br />
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==Notes==<br />
Just trying to simplify and understand the process and these are some of my notes !(z3417363)<br />
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The inactive Wnt Pathway In a normal cell:<br />
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In most normal cells the Wnt pathway is inactive. In the cytosol , the destruction complex is formed from the proteins beta catenin, GSK3 beta, Axin,APC, Ck1-alpha. The ubiquitin ligase beta TRCP is able to bind to beta catenin and transfer short ubiquitin peptides to beta-catenin. In other words the beta-catenin is phosphorolated and this beta catenin can then bound and be by a complex of protease (proteasome) . Thus a low level of cellular beta catenin is achieved. <br />
Therefore no beta catenin reaches the nucleus and the transcription factor of the TCF LEF family along with other proteins (groucho) binds to DNA and inhibits gene expression.<br />
So essentially when WnT is inactive, beta canenin is destroyed and does not reach nucleus and transcription is inhibited. <br />
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The Active Wnt Pathway in a normal cell.<br />
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Extracellular(outside cell) Wnt binds with the membrane receptor frizzled (FZD). The wnt pathway is activated and activates the cytosolic protein "dishevelled"(DSH) which induces dissociation of the protein destruction complex. Because the protein complex is destroyed beta- catenin is no longer modified by unbiquitin peptides/phosporolated and is not destroyed. Since the supply of beta catenin continues the level of beta catenin rises, first in the cytosol and later in the nucleus. Once the beta catenin reaches the nuclue it binds to the TCF LEF transcription factor which changes them from a transcriptional repressor into an activator. TCF itself activates an RNA polymerase which induces gene transcription.<br />
So essentially WnT starts gene transcription by allowing beta catenin to reach the nucleus.<br />
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This is actually very similar to a tumour cell where the mutation of the protein complex also inhibits the destruction of beta catenin and allows it to grow in quantity and reach the nucleus and start gene expression. However this is not uncontrolled and can be compared to a car travelling with no brakes. Ultimately this abnormal proliferation leads to malignant adenocarcinoma (cancer).<br />
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Use pubmed, biomedcentral journals==you can find it on pubmed just plug in the title and you will get the pubmed number>BMC developmental biology journal, journal of cell biology(cant use last 6months of research), proceeding national academy of science(can only use after 6months), public library of science omim<br />
include research labs, animations<br />
use the help tab<br />
where the terminlogy came from <br />
this is a student drawn image , based upon and give the reference</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2016_Group_Project_6&diff=249632
Talk:2016 Group Project 6
2016-10-06T16:38:28Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016discussionheader}}<br />
=Peer Review=<br />
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<u>Group 6:</u><br />
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<b>Positive aspects of the project and suggested improvements:</b><br />
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The authors of group 6 have created a variety of subheadings related to the TGF-beta signalling pathway, including the nature of the growth factor, its mechanism of action, history and emerging research (criteria 1). Authors have also provided two diagrams related to TGF-beta signalling which reinforces the description of TGF signalling provided (criteria 2). These diagrams allow for a much simpler interpretation of the signalling process described and assist in teaching at the peer level (criteria 4). It appears that the authors are beginning to conduct investigations into new research surrounding TGF-beta signalling, thus indicating that they are attempting to research beyond formal teaching activities (criteria 5). <br />
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Whilst it is excellent that multiple subheadings have been provided, a possible improvement would be to include a much larger variety of subheadings which cover the scope of TGF-beta’s role in embryonic development, abnormalities, types of TGF receptors and animal models. This may allow audiences to understand the big picture surrounding this signalling pathway which will assist in the understanding of the information already provided. Another improvement to this page would be to include more images under different subheadings. One example would be to include an image or table showing the history of discovery surrounding discovery of this signalling pathway. <br />
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<b>Negative aspects of the project and suggested improvements:</b><br />
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Although there were positive aspects of this project, there were also numerous negative aspects which may be improved. One key negative feature of the page was that the authors did not discuss the role of TGF-beta signalling in the context of embryonic development, hence meaning they failed to meet criteria 6. To ensure that this criterion is met, authors may conduct research into the involvement of TGF-beta in specific processes that occur during embryonic development, perhaps organ development and growth of different primitive structures. In addition, whilst the authors have provided a history of the TGF-beta signalling pathway, the history appears to be very brief. Thus an improvement which may be implemented would be to include a more extensive background regarding the history of discovery of the pathway. It was also noticed that no tables were utilised within the page. A possible improvement would be to include a table describing different abnormalities and their causes in the context of disruption of the TGF-beta pathway. A table may also be utilised to describe different subtypes of TGF-beta receptors as well as their functions during embryonic development. Tables may be utilised as they will assist in the process of teaching at the peer level (criteria 4), particularly because they convey information in an orderly and organised manner. <br />
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The authors of this project also failed to meet criteria 3, in that only one source was referenced in the process of the signalling pathway and also no in-text citations were provided. In addition, authors failed to reference the image file named, “Process of TGF-beta signalling pathway 01”. It is vital that all sources are referenced correctly in order to ensure that the copyright laws regarding the use of information are adhered to. The final negative aspect of the project was that the page did not flow very well, in that subheadings were arranged in a disorderly fashion. An example of this is the inclusion of the subheading labelled, “history of TGF-beta signalling pathway”, towards the end of the page. Since such a subheading provides a background surrounding the pathway, a possible improvement would be to include this subheading at the beginning of the page. By ensuring the orderliness of the page, this creates a sense of coherency between subheadings, thus making the page more appealing and engaging.<br />
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===Group 6===<br />
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It was good to see some progress being made on the project with the development of some subheadings and the inclusion of an image. In saying this, a better selection of headings and sub-headings could be developed to break down the topic of TGF beta signaling pathway. I think the sub-headings provided under the general heading of ‘Introduction’ could form the main headings of this research project and they could then be further broken down into various subheadings. In addition, the subheading of TGF-beta could be eliminated and this definition could be incorporated into the glossary or general introduction of the topic instead. Furthermore, more focus is needed on the influence of this pathway on embryological development and the abnormalities caused by mutations to the pathway and its components. For example, there has been mention of the effect of TGF-beta in ‘development of the embryo and adult organism, as well as cell growth, immune function and hormone secretion’ but further discussion has not been pursued. <br />
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Though a good description of the ‘process of TGF-beta signaling pathway’ has been provided, it could be further improved by referencing the images included in this section in your text (e.g. refer to Figure 1) to aid one’s understanding of the concept being explored. In addition, a timeline of events could be provided to explore the history of this pathway and it would be appropriate to begin with the discovery of TGF-beta. To a reader, information on ‘transformed or malignant cells’ seems unrelated to the TGF-beta signaling pathway even though it may be in fact be related, due to lack of discussion of this pathway or TGF-beta in this description. In regards to the section on ‘Limitations’, what types of limitations are you trying to explore? Limitations in research? This could be better defined by appropriately allocating subheadings to each of the sections.<br />
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Though you are heading in the right direction, spending time to produce a basic layout of your project by creating appropriate headings and subheadings would be useful in breaking down the concepts needed to be explored in this pathway. This could be achieved by communicating with group members through the discussion page and providing feedback and suggestions. In addition, greater focus is required in referencing and citing your work to ensure researchers and authors are acknowledged for their work. Also, by exploring animal models of the TGF-beta pathway and the effect of this research in understanding this pathway in humans and its influence on embryological development, you could greatly increase the quality of your work. You could also try and make your project more interactive and engaging through the inclusion of tables, images and diagrams. I hope this helps! Good luck!<br />
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=== Group 6 Critical Assessment===<br />
It is great to see an in-depth overview of the TGF beta Signalling pathway and it’s mechanism of action. The page is off to a great start and with a few key improvements it can turn into a successful one! Firstly, I like the use of images to aid the reader in understanding the content better should they be a visual learner. By reading the text on the way the pathway works, it is clear it is a complicated process hence a suggestion would be to add short clips/animations to simplify it for the viewer. <br />
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Under your introduction an attempt has been made to briefly highlight the main features of the pathway, however a negative of this section is that a lot of the content is basically listed. For example it is mentioned TGF-beta is part of a larger TGF superfamily comprising of different members such as activins and GDFs. Instead of listing, try presenting your information in a different format such as a table with s few columns stating the member, it’s function, and possibly what a mutation could lead to. <br />
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Additionally it is also stated that TGF beta has certain functions such as controlling angiogenesis however doesn’t expand on the ‘other’ functions it has. To turn this into a positive, dedicate different sections on how the pathway is involved in angiogenesis, hormone secretion, proliferation etc. If there are too many functions to fit onto the page, you could shift a few to your ‘Further Reading’ section as an option if the reader would like to explore further into the pathway’s functions, or construct a hidden table that the viewer can expand if they wish to. <br />
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In order to satisfy criteria 3, in text citations should be incorporated within text so the viewer has an option to access the article if they find the statement interesting. A reference list has been posted with a few references however ensure they are cited in the correct format. Overall a great start!<br />
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===Group 6 Peer Assessment===<br />
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In this project page a good start has been made with the inclusion of images to compliment the signalling pathway description. Appropriate abbreviations appear to be used, where the full name is used first. Also the additions of a glossary and further reading subheading is a nice touch, which should allow for better understanding of the topic should the reader want more information. In terms of the diversity of the subheadings though, it seems that a lot more could be added, such as animal models used to research the signalling pathway and also possibly abnormalities that may arise from the errors or mutations in the pathway. It is probably wise to also add a section regarding embryological development and what role TGF beta signalling pathway has in it, which should help provide context to the abnormalities section when added. <br />
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The usage of pictures is appropriate for the section it has been put in, and compliments the signal transduction pathway description well, but the picture labelled “Process of TGF-beta signalling pathway” does not appear to be referenced or have the appropriate copyright under it. There is also no legend for this picture to briefly describe it. Also for most of the page there are limited to no references, where for the signalling pathway section, it appears your groups has used websites rather than peer reviewed articles as a source. The websites are probably good starting points to get a general idea of the pathway, but it is probably better if you find peer reviewed papers to cite, which potentially the websites you have used have cited. Also when citing it is best to use in text citation such that the reader can easily see which paper you are referring to when describing certain facts. <br />
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Also in your groups signalling section, it is mentioned that SMAD when activated, recruits various transcriptional regulators that control expression of numerous genes. This is quite vague and is probably a good idea to mention some of these factors, and also what genes they regulate and the importance of such genes. Doing this should also provide your group with a good link to the embryological development section with regards to TGF-beta signalling.<br />
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It still seems that overall there is a lot of work to be done on your groups page, but a good start and effort has been made to include various images and also subheadings. I feel that if your group incorporates some of the suggested subheadings described above, and other feedback mentioned, the page should be greatly improved.<br />
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===Group 6 – TGF-beta===<br />
You guys have made a good start to the project identifying some important subheadings introducing the TGF-beta signaling pathway, outlining its history, current research and limitations (which may be more appropriately labeled as abnormalities.) However, I do think the structure of these should be revised, what I mean by this is that you should create more levels of headings (as currently all the headings are located under the larger heading of introduction.) Furthermore, it terms of the headings, I think you need to introduce the signaling pathway, then discuss the history of its discovery, then discuss the specific mechanisms behind the pathway, its role in embryonic development (which is a very important aspect in order to relate your project back to what we are learning in the lectures and tutorials), then animal models and abnormalities. You have chosen to include some images which appear to be useful for explaining the signaling pathway, however I think it is important to refer to them in your text, as well as appropriately referencing them with the copyright from the original source (as the larger one is missing this information.) <br />
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Some negative aspects of this project are the lack of appropriate references, there are no in-text citations and the identified sources that have been used appear to be websites. Remember that most of the information, if not all should be acquired from primary research articles (supplemented with the occasional review article.) Furthermore, similar to other projects, in order to make your page more engaging you could look into including tables (say for the history or summary of receptor subtypes), more images, YouTube links or animations, or an interactive quiz.<br />
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In conclusion it seems that there is still a lot of work to be completed on this page before it is to be submitted, however you have made a successful start. The main criticisms are regarding revisiting the subheadings and including the role of embryonic development as I think this is really critical to the project, as well as adding more information to the page in general. In saying that it appears you guys are heading in the right direction!<br />
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===Group 6 Peer Assessment===<br />
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Positive aspects of the project and improvements:<br />
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Upon reviewing the page I can see a number of headings and subheadings such as the nature of the growth factor, its mechanism of action, history and emerging research. But to be critical, a range of other headings is necessary to ensure all bases are covered when researching and providing the relevant information. This will help in satisfying the requirements for criteria 1 and 2. It is good to see the addition of a diagram to your project as it is a requirement for criteria 2. This provided a visual aid that kept me interested to find out more about the topic while simultaneously making it easier to understand the theory behind the process of TGF Beta signalling pathway. It is also great to see the current research and limitations as this shows that you are going beyond the scope of the required criteria and researching ahead to provide that extra bit of information. This in turn is a great way to satisfy criteria 5.<br />
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Negative aspects of the project and improvements:<br />
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Although there are a few positives in the project, there are a number of negatives which can be improved upon to ensure a coherent project is created. Firstly, it is advised to put the heading “history of TGF- beta signalling pathway at the top” with the introduction as this is an introductory section and should be addressed initially on the page. This will allow you to create a more flowing page which also looks nice. Secondly, it would be advised to add more images and tables as it is a requirement for criteria 2. By doing this you will keep the reader engaged and wanting to find out more about the chosen topic. In saying that, you already have a couple of images but not referenced. It is imperative to correctly cite and reference these images as failure to do so will result in a breach of copyright laws. <br />
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Another critique is to add more subheadings with a range of different aspects of the signalling pathway being explored. It is recommended that you dedicate a chunk of your project to describing the pathway in detail and its role in embryonic development and abnormalities relating to mutations caused by the pathway. This will ensure you answer criteria 6 as it is a great deal of the report. It is also advised to put the history section under the introduction section as placing it in the middle of the project is a bit out of place and inhibits the flow of the information from one subheading to another. Also, the history section can be improved by adding more information as there have been more findings in this research topic since the 1970s. An addition of glossary is also needed for terms such as “peptide”, “cytokine”, “angiogenesis”, “protein kinase” etc. This will aid readers understand terms that they previously have not encountered and allow them to correctly understand the context of the information. <br />
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It has also come to my attention that there are little to no references or in text citations. By adding information without correctly giving the authors credit is a breach of copyright laws and must be done urgently. Overall, the project shows signs of progress with a number of positives. By reflecting on the negative aspects and acting upon it, it is certain that high marks are in order.</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2016_Group_Project_5&diff=249630
Talk:2016 Group Project 5
2016-10-06T16:37:37Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016discussionheader}}<br />
=Peer Review=<br />
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<br><br />
<u>Group 5: </u><br />
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<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br />
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Upon reviewing this page, it is clear that group 5 has provided numerous headings and subheadings related to Tbx-genes ranging from origins of the genes, their function in embryonic development, abnormalities, history and animal models (criteria 1 and 6). In doing so, the group has also ventured to provide an in-depth explanation of each subheading. Take for example the subheading named, “limb development”, the authors have provided an in-depth description into the role of T-box transcription factors in limb development whilst utilising a diagram to reinforce this description (criteria 2). It also appears that in-text citations have been correctly used to reference the sources of data in most cases (criteria 3). The authors have utilised diagrams and a table to describe various components of the T-box gene ranging from the different types of T-box genes to its mechanisms in embryonic development (criteria 4). The extensive use of diagrams allows the audience to develop a holistic understanding of the various subheadings included, as these diagrams convey the description provided in a visual manner (criteria 5). It is also evident that the group has conducted research into animal models and evolution of the T-box gene, thus demonstrating that the group has investigated areas of research beyond formal teaching activities (criteria 5).<br />
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Improvements which may be made to this page would be to include a timeline regarding the history of the T-box family, as this will display the information in a much more organised and appealing manner. Another improvement which may be made would be to include a YouTube video to introduce the signalling process in development, such as in cardiac and limb development for example. In order to make the wikipage interactive, a further improvement which may be made would be to include a set of multiple choice questions at the end of the page which ask questions about the content covered. <br />
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<b>Negative aspects of the project and suggested improvements:</b><br />
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Alongside the various positive aspects of this project, there are few negative aspects. A negative aspect identified includes the use of images from Wikipedia pages more than once. It was stated that only one Wikipedia page was allowed to be included as a source. Therefore a suggestion would be to obtain images and data from research articles rather than from Wikipedia pages, as research articles are often a more reliable source of data. It was also noticed that images were not utilised to describe different abnormalities associated with the TBX gene, hence a possible improvement would be to include images depicting such abnormalities. These images may make this section of the page more appealing and engaging to audiences. <br />
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It was also noticed that the image titled “Evolution of the T box gene family”, was incorrectly referenced. Therefore, it is suggested that the authors of the project ensure that the original author of the image are correctly referenced to ensure that copyright laws are not breached. The final negative aspect of the project was that the “Ancient origins and evolution of the T-box gene family” subheading appeared out of place in the page. Therefore a possible improvement would be to include evolution of the T-box gene under the “Origins of the T-box gene” subheading at the beginning of the page as this will create a sense of consistency in the page.<br />
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===Group 5===<br />
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First of all, well done on making significant progress on your project! You have addressed all aspects of the pathway involving T-Box genes through subdivision into various headings and subheadings. I particularly liked how there was an inclusion of the specific T-Box gene affected in each of the abnormalities in the subheading itself. The only suggestion I would make is to combine the ‘Ancient origins and evolution of the T-Box gene family’ section with the origins of the ‘T-Box genes’ section to provide a more coherent description of the history of these pathway. You could even form a table to create a timeline of events. In addition, I think it would be beneficial to include the ‘What does T-Box mean?’ as an introduction to the ‘origins of the T-box genes’ section as there is overlap between these sections. <br />
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The use of a table to describe the main T-box genes was helpful in providing a brief overview of the components of the pathway and their influence in embryological development. In addition, the link between T-Box genes and embryonic development has been explored considerably. In saying this, greater attention to detail must be paid to explaining abbreviations to aid one’s understanding of the concepts being discussed. For example, what is NKX2-5, Shh and OFT? Though you’ve explained that RA stands for retinoic acid in the ‘Organisms used in animal models for T-Box’ section, this same explanation is not provided in the ‘Limb development’ section where you have discussed that ‘RA and Shh both induced Tbx2’. These small changes will significantly improve the quality of your work. <br />
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The inclusion of abnormalities provides great insight into the role of T-Box genes in development. In saying this, though you have explored the effect of the mutation of these genes in animal models, more information is required to explain the effect of these mutations in humans and how they come about. Furthermore, under the heading of ‘Animal models’ there has been discussion mainly of the ‘brachyury gene’ which seems unrelated to animal models due to the lack of a proper introduction. I found the following section (organisms used in animal models for T-Box) to be a better introduction to the topic of animal models. In addition, there has been mention of a number of animal models ‘Drosophila, Xenopus, zebrafish, avians, and mice’ yet only marsupials and amphioxus has been discussed. This could be potentially misleading to readers. <br />
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Overall, a fantastic effort has been made. Not only have you touched upon nearly every section of the project, but have included some excellent diagrams and tables which aid understanding of this pathway. In saying this, it is noted that two Wikipedia images have been used though it has been suggested that only one of the images utilised can be from Wikipedia. All information provided was also appropriately referenced and cited. In addition, I think it would be useful to utilise the discussion page to encourage interaction between group members as it allows individuals to provide feedback and suggestions. Hope this helps!<br />
<br />
===Group 5 Critical Assessment===<br />
Well done on constructing a thorough Wiki page on the topic of T-box Genes and their Signalling! Viewing the page it is evident numerous headings and subheadings have been provided to accommodate for the large amount of information gathered. Starting off with the introduction I like how you have included a section on what T’-box exactly means, however the information provided in this section talks about the history significantly, hence to turn this into a positive I would suggest adding a table or timeline outlining the major events and discoveries in the past to present this information in a complete, meaningful way. This issue is also seen with the section ‘Origins of the T-box genes’ where major discoveries are highlighted and in which year they occurred. This information can also merge with the history timeline/table. <br />
<br />
Within the ‘What does T-box mean?’ section you have also added information on which animal studies were undertaken for the discoveries. To avoid spreading of information and causing confusion for the reader, you could either construct a table to show which animal study was completed in which year, and what discovery it led to as 3 columns, or bring this information down to the section ‘Animal Models’. In saying that, you have attempted to utilize a table and the table works very well with the topic of the different T-box genes, and would prove great help for the viewer. <br />
<br />
It is great to see T-box genes and Signalling has been explored further in the field of embryonic development. Extensive information is provided with good use of in- text citations, allowing the reader to navigate to relevant articles. The ability to navigate could be further improved by providing an accessible link to the ‘Abnormalities’ section in a case where you are directing the reader to the section for further information, instead of plain text. Beneath each section for e.g. ‘Limb Development’ Pubmed links have been provided to relevant articles, which is a fantastic idea, however the links have no indication whatsoever of what the article is about. You could add a sentence each next to the links briefly stating what the article is exploring in relation to limb development. <br />
<br />
Overall with a few more images, possibly some interactive components such as clips, and a knowledge testing short exam or quiz this Wiki page will stand out. Remember to ensure your information flows well by placing it within appropriate sections!<br />
<br />
===Group 5 Peer Assessment===<br />
<br />
It is quite clear that what has been provided in your wiki page is extensive and well researched. The inclusion of tables summarizing the different T-box genes although extensive, is very concise and easy to read. I feel that this table really links all the elements of your page together, where you have included its function and related it to embryological development and abnormalities which you go on later to elaborate in other sections. I feel this really complements the introduction and gives a good feel for what’s to come in the rest of the page. The addition of what the term T-box means also is a nice touch, giving context and some history regarding the name. <br />
<br />
Your origins section of T-box is quite well outlined, but as mentioned in your page, having a timeline with critical points of discovery with regards to the genes would probably be more beneficial as it would be a lot easier to read a see the time points as a whole. That being said, having the timeline alongside your outline would probably work well, as your outline can serve to elaborate on the timeline. With regards to your subheadings, it seems to they are quite extensive and cover practically all the key components of the T-box genes, and it is also good to see that there is a glossary subheading in place. Content wise there seems to be limited to no issues, but with regards to abbreviations, I have found that the usage hasn’t always been after the fact of providing the full name first. For example, bone morphogenic protein’s abbreviation is used consistently throughout the first part of the wiki page, but it is only described by its full name and then abbreviation later on. This is something you should check out and fix by either adding the full name the first time the abbreviation is used, or adding all these terms to the glossary. <br />
<br />
With regards to the pictures they all seem to compliment the sections well and are quite plentiful. That being said though the picture in the “Marsupial forelimb development” does not appear to have the copyright information regarding to its usage, and referencing does not appear to be in full. This is also the same for the picture under the subheading “Organisms used in animal models for T-box”. Other than that the referencing is perfectly fine within the text.<br />
<br />
Overall this project is really good and without any major flaws when it comes to the content. A few touch ups here and there with regards to my suggestion above, and your project should be good to go along as the quality is kept at this level.<br />
<br />
<br />
===Group 5 – T-Box===<br />
First impressions alone it is extremely clear that Group 5 has thoroughly researched this topic have tried hard to include many diagrams and tables to help separate their information up in order to more successfully convey the information across to the reader. Positive aspects of this project include the well-defined subheadings, making the navigation through the page very easy. The introduction is informative and introduces the following subheadings of the project well. The inclusion of what does T-Box mean is also interesting, setting you apart from the other projects. One of the best aspects of the project would have to be the summary table of the main T-box genes, which includes its main expression sites, its function and abnormalities relevant to the specific gene. You have made a note to include a timeline for the history of the T-Box gene, which I think would be successful in summarizing the scientific advances since its discovery, and also help to break up paragraphs of writing. The project appears to be referenced correctly using in-text citations, only query is whether the links to the PMID articles say in the bottom of cardiac and limb development are references or just articles in which you haven’t written on yet and will be referenced appropriately when you do later. The inclusion of a glossary is also a good idea just to help define and explain some of the more difficult terms mentioned. <br />
<br />
As for negative aspects of the project, there wasn’t too many. Like for every project, in terms of making it more interactive it might be a good idea to include a YouTube video or animation of the signaling pathway or its role in a specific developmental process, as well as your own hand-drawn image just to fulfill the necessary criteria of this assignment. Furthermore, with some of the smaller images that don’t go the full width of the page, it might be a nice idea to align them to the right as a thumbnail next to their relevant text, so readers see them whilst reading about it. Also remember to make a reference the image you have chosen in your text to emphasise its importance to what you are actually talking about. Although the subheading “good places to look” might just be something for you guys while researching, I think that you could utilize this by including various links with more information on the relevant topics of which you have discussed. This would help to make you page more interactive as well.<br />
<br />
This project appears to be extremely well done and is definitely one of the strongest. Most of the criticisms are regarding the formatting of the page and making it more interactive for the reader. All in all this is very well researched project! <br />
<br />
<br />
===Group 5 Peer Assessment===<br />
<br />
Positive aspects of the project and improvements:<br />
<br />
Upon reviewing the page, it is evident that there has been a lot of research put in this project. Initially, there is evidence of a range of headings and subheadings which allowed the navigation from one aspect of the project to another extremely easy. This allowed me to confirm that the project is about T-box genes and their signalling. Secondly, it was excellent to see a range of images, tables and graphs as they provided visual aids to learn more about the topic and in general made it easier to accumulate information. Also it was good to see that these tables and images were correctly cited and referenced at the end which meant that there was no breach of copyright laws. <br />
<br />
Also, throughout the project there was sufficient amount of information in each subheading which meant that the reader gained all relevant information pertaining to the section that they are reading. It was also great to see a range of abnormalities being added to the project. This meant that you have went above and beyond the scope of the assessment and researched that extra bit to provide additional information about the signalling pathway and complications arising from any mutations. This meant that you successfully satisfied criteria 5 and thus a more rounded project. <br />
<br />
Negative aspects of the project and improvements:<br />
<br />
This project certainly contains a range of positives but there were minimal negatives that can easily be amended in order to achieve a very high mark. I noticed that there was more than 1 image being used from Wikipedia and the criterion clearly says that a maximum of 1 was allowed. This is not a big deal but just in case there is harsh marking and penalties, it is advised to replace the additional image with another image. In addition, it would be useful to add a glossary of all the terms that one may find confusing such as “homologues”, “heterozygous”, “homology”, “notochord” etc. This in turn will provide the reader with enough information to understand the context of the project and in turn keep them engaged.<br />
<br />
Another negative aspect of the project was that the subheading “Ancient origins and evolution of the T-box gene family” randomly appearing nearing the end of the project. This looked a bit out of place and not flowing with the rest of the passage. To correct this it would be advised to add this to the start of the page with the “Origin of the T-box genes” section just so the information clearly flows from one topic to another without creating confusion. Overall, this project is coming along quite nicely. It is evident that a lot of research has been put into constructing a coherent and succinct project but also have the visual cues to back up the main aspects. To maximise marks, it is recommended to reflect on the feedback and correct the minor mistakes. <br />
<br />
<br />
<br />
Some searches to get us started:<br />
[http://www.ncbi.nlm.nih.gov/sites/gquery?term=t-box ''T-box'']<br />
[http://www.ncbi.nlm.nih.gov/sites/gquery?term=tbx ''tbx'']<br />
<br />
[[User:Z5020373|Z5020373]] ([[User talk:Z5020373|talk]]) 14:44, 26 August 2016 (AEST)<br />
PMID 25294936 - a relatively recent article that provides background info on the T-box gene family<br />
PMID 16285859<br />
<br />
[[User:Z3516832|Z3516832]] ([[User talk:Z3516832|talk]]) 14:52, 26 August 2016 (AEST)<br />
http://www.columbia.edu/itc/hs/medical/humandev/2007/HD15/HD15.pdf<br />
<br />
[[User:Z5020373|Z5020373]] ([[User talk:Z5020373|talk]]) 11:32, 16 September 2016 (AEST) Does anyone know how to draw up a table on the page? Thanks.</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2016_Group_Project_5&diff=249628
Talk:2016 Group Project 5
2016-10-06T16:37:03Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016discussionheader}}<br />
=Peer Review=<br />
<br><br />
<br><br />
<u>Group 5: </u><br />
<br><br />
<br><br />
<br />
<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Upon reviewing this page, it is clear that group 5 has provided numerous headings and subheadings related to Tbx-genes ranging from origins of the genes, their function in embryonic development, abnormalities, history and animal models (criteria 1 and 6). In doing so, the group has also ventured to provide an in-depth explanation of each subheading. Take for example the subheading named, “limb development”, the authors have provided an in-depth description into the role of T-box transcription factors in limb development whilst utilising a diagram to reinforce this description (criteria 2). It also appears that in-text citations have been correctly used to reference the sources of data in most cases (criteria 3). The authors have utilised diagrams and a table to describe various components of the T-box gene ranging from the different types of T-box genes to its mechanisms in embryonic development (criteria 4). The extensive use of diagrams allows the audience to develop a holistic understanding of the various subheadings included, as these diagrams convey the description provided in a visual manner (criteria 5). It is also evident that the group has conducted research into animal models and evolution of the T-box gene, thus demonstrating that the group has investigated areas of research beyond formal teaching activities (criteria 5).<br />
<br><br />
<br><br />
Improvements which may be made to this page would be to include a timeline regarding the history of the T-box family, as this will display the information in a much more organised and appealing manner. Another improvement which may be made would be to include a YouTube video to introduce the signalling process in development, such as in cardiac and limb development for example. In order to make the wikipage interactive, a further improvement which may be made would be to include a set of multiple choice questions at the end of the page which ask questions about the content covered. <br />
<br><br />
<br><br />
<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
<br />
Alongside the various positive aspects of this project, there are few negative aspects. A negative aspect identified includes the use of images from Wikipedia pages more than once. It was stated that only one Wikipedia page was allowed to be included as a source. Therefore a suggestion would be to obtain images and data from research articles rather than from Wikipedia pages, as research articles are often a more reliable source of data. It was also noticed that images were not utilised to describe different abnormalities associated with the TBX gene, hence a possible improvement would be to include images depicting such abnormalities. These images may make this section of the page more appealing and engaging to audiences. <br />
<br><br />
<br><br />
<br />
It was also noticed that the image titled “Evolution of the T box gene family”, was incorrectly referenced. Therefore, it is suggested that the authors of the project ensure that the original author of the image are correctly referenced to ensure that copyright laws are not breached. The final negative aspect of the project was that the “Ancient origins and evolution of the T-box gene family” subheading appeared out of place in the page. Therefore a possible improvement would be to include evolution of the T-box gene under the “Origins of the T-box gene” subheading at the beginning of the page as this will create a sense of consistency in the page.<br />
<br><br />
<br><br />
<br />
===Group 5===<br />
<br />
First of all, well done on making significant progress on your project! You have addressed all aspects of the pathway involving T-Box genes through subdivision into various headings and subheadings. I particularly liked how there was an inclusion of the specific T-Box gene affected in each of the abnormalities in the subheading itself. The only suggestion I would make is to combine the ‘Ancient origins and evolution of the T-Box gene family’ section with the origins of the ‘T-Box genes’ section to provide a more coherent description of the history of these pathway. You could even form a table to create a timeline of events. In addition, I think it would be beneficial to include the ‘What does T-Box mean?’ as an introduction to the ‘origins of the T-box genes’ section as there is overlap between these sections. <br />
<br />
The use of a table to describe the main T-box genes was helpful in providing a brief overview of the components of the pathway and their influence in embryological development. In addition, the link between T-Box genes and embryonic development has been explored considerably. In saying this, greater attention to detail must be paid to explaining abbreviations to aid one’s understanding of the concepts being discussed. For example, what is NKX2-5, Shh and OFT? Though you’ve explained that RA stands for retinoic acid in the ‘Organisms used in animal models for T-Box’ section, this same explanation is not provided in the ‘Limb development’ section where you have discussed that ‘RA and Shh both induced Tbx2’. These small changes will significantly improve the quality of your work. <br />
<br />
The inclusion of abnormalities provides great insight into the role of T-Box genes in development. In saying this, though you have explored the effect of the mutation of these genes in animal models, more information is required to explain the effect of these mutations in humans and how they come about. Furthermore, under the heading of ‘Animal models’ there has been discussion mainly of the ‘brachyury gene’ which seems unrelated to animal models due to the lack of a proper introduction. I found the following section (organisms used in animal models for T-Box) to be a better introduction to the topic of animal models. In addition, there has been mention of a number of animal models ‘Drosophila, Xenopus, zebrafish, avians, and mice’ yet only marsupials and amphioxus has been discussed. This could be potentially misleading to readers. <br />
<br />
Overall, a fantastic effort has been made. Not only have you touched upon nearly every section of the project, but have included some excellent diagrams and tables which aid understanding of this pathway. In saying this, it is noted that two Wikipedia images have been used though it has been suggested that only one of the images utilised can be from Wikipedia. All information provided was also appropriately referenced and cited. In addition, I think it would be useful to utilise the discussion page to encourage interaction between group members as it allows individuals to provide feedback and suggestions. Hope this helps!<br />
<br />
===Group 5 Critical Assessment===<br />
Well done on constructing a thorough Wiki page on the topic of T-box Genes and their Signalling! Viewing the page it is evident numerous headings and subheadings have been provided to accommodate for the large amount of information gathered. Starting off with the introduction I like how you have included a section on what T’-box exactly means, however the information provided in this section talks about the history significantly, hence to turn this into a positive I would suggest adding a table or timeline outlining the major events and discoveries in the past to present this information in a complete, meaningful way. This issue is also seen with the section ‘Origins of the T-box genes’ where major discoveries are highlighted and in which year they occurred. This information can also merge with the history timeline/table. <br />
<br />
Within the ‘What does T-box mean?’ section you have also added information on which animal studies were undertaken for the discoveries. To avoid spreading of information and causing confusion for the reader, you could either construct a table to show which animal study was completed in which year, and what discovery it led to as 3 columns, or bring this information down to the section ‘Animal Models’. In saying that, you have attempted to utilize a table and the table works very well with the topic of the different T-box genes, and would prove great help for the viewer. <br />
<br />
It is great to see T-box genes and Signalling has been explored further in the field of embryonic development. Extensive information is provided with good use of in- text citations, allowing the reader to navigate to relevant articles. The ability to navigate could be further improved by providing an accessible link to the ‘Abnormalities’ section in a case where you are directing the reader to the section for further information, instead of plain text. Beneath each section for e.g. ‘Limb Development’ Pubmed links have been provided to relevant articles, which is a fantastic idea, however the links have no indication whatsoever of what the article is about. You could add a sentence each next to the links briefly stating what the article is exploring in relation to limb development. <br />
<br />
Overall with a few more images, possibly some interactive components such as clips, and a knowledge testing short exam or quiz this Wiki page will stand out. Remember to ensure your information flows well by placing it within appropriate sections!<br />
<br />
===Group 5 Peer Assessment===<br />
<br />
It is quite clear that what has been provided in your wiki page is extensive and well researched. The inclusion of tables summarizing the different T-box genes although extensive, is very concise and easy to read. I feel that this table really links all the elements of your page together, where you have included its function and related it to embryological development and abnormalities which you go on later to elaborate in other sections. I feel this really complements the introduction and gives a good feel for what’s to come in the rest of the page. The addition of what the term T-box means also is a nice touch, giving context and some history regarding the name. <br />
<br />
Your origins section of T-box is quite well outlined, but as mentioned in your page, having a timeline with critical points of discovery with regards to the genes would probably be more beneficial as it would be a lot easier to read a see the time points as a whole. That being said, having the timeline alongside your outline would probably work well, as your outline can serve to elaborate on the timeline. With regards to your subheadings, it seems to they are quite extensive and cover practically all the key components of the T-box genes, and it is also good to see that there is a glossary subheading in place. Content wise there seems to be limited to no issues, but with regards to abbreviations, I have found that the usage hasn’t always been after the fact of providing the full name first. For example, bone morphogenic protein’s abbreviation is used consistently throughout the first part of the wiki page, but it is only described by its full name and then abbreviation later on. This is something you should check out and fix by either adding the full name the first time the abbreviation is used, or adding all these terms to the glossary. <br />
<br />
With regards to the pictures they all seem to compliment the sections well and are quite plentiful. That being said though the picture in the “Marsupial forelimb development” does not appear to have the copyright information regarding to its usage, and referencing does not appear to be in full. This is also the same for the picture under the subheading “Organisms used in animal models for T-box”. Other than that the referencing is perfectly fine within the text.<br />
<br />
Overall this project is really good and without any major flaws when it comes to the content. A few touch ups here and there with regards to my suggestion above, and your project should be good to go along as the quality is kept at this level.<br />
<br />
<br />
===Group 5 – T-Box===<br />
First impressions alone it is extremely clear that Group 5 has thoroughly researched this topic have tried hard to include many diagrams and tables to help separate their information up in order to more successfully convey the information across to the reader. Positive aspects of this project include the well-defined subheadings, making the navigation through the page very easy. The introduction is informative and introduces the following subheadings of the project well. The inclusion of what does T-Box mean is also interesting, setting you apart from the other projects. One of the best aspects of the project would have to be the summary table of the main T-box genes, which includes its main expression sites, its function and abnormalities relevant to the specific gene. You have made a note to include a timeline for the history of the T-Box gene, which I think would be successful in summarizing the scientific advances since its discovery, and also help to break up paragraphs of writing. The project appears to be referenced correctly using in-text citations, only query is whether the links to the PMID articles say in the bottom of cardiac and limb development are references or just articles in which you haven’t written on yet and will be referenced appropriately when you do later. The inclusion of a glossary is also a good idea just to help define and explain some of the more difficult terms mentioned. <br />
<br />
As for negative aspects of the project, there wasn’t too many. Like for every project, in terms of making it more interactive it might be a good idea to include a YouTube video or animation of the signaling pathway or its role in a specific developmental process, as well as your own hand-drawn image just to fulfill the necessary criteria of this assignment. Furthermore, with some of the smaller images that don’t go the full width of the page, it might be a nice idea to align them to the right as a thumbnail next to their relevant text, so readers see them whilst reading about it. Also remember to make a reference the image you have chosen in your text to emphasise its importance to what you are actually talking about. Although the subheading “good places to look” might just be something for you guys while researching, I think that you could utilize this by including various links with more information on the relevant topics of which you have discussed. This would help to make you page more interactive as well.<br />
<br />
This project appears to be extremely well done and is definitely one of the strongest. Most of the criticisms are regarding the formatting of the page and making it more interactive for the reader. All in all this is very well researched project! <br />
<br />
<br />
===Group 5 Peer Assessment===<br />
<br />
Positive aspects of the project and improvements:<br />
<br />
Upon reviewing the page, it is evident that there has been a lot of research put in this project. Initially, there is evidence of a range of headings and subheadings which allowed the navigation from one aspect of the project to another extremely easy. This allowed me to confirm that the project is about T-box genes and their signalling. Secondly, it was excellent to see a range of images, tables and graphs as they provided visual aids to learn more about the topic and in general made it easier to accumulate information. Also it was good to see that these tables and images were correctly cited and referenced at the end which meant that there was no breach of copyright laws. <br />
<br />
Also, throughout the project there was sufficient amount of information in each subheading which meant that the reader gained all relevant information pertaining to the section that they are reading. It was also great to see a range of abnormalities being added to the project. This meant that you have went above and beyond the scope of the assessment and researched that extra bit to provide additional information about the signalling pathway and complications arising from any mutations. This meant that you successfully satisfied criteria 5 and thus a more rounded project. <br />
<br />
Negative aspects of the project and improvements:<br />
<br />
This project certainly contains a range of positives but there were minimal negatives that can easily be amended in order to achieve a very high mark. I noticed that there was more than 1 image being used from Wikipedia and the criterion clearly says that a maximum of 1 was allowed. This is not a big deal but just in case there is harsh marking and penalties, it is advised to replace the additional image with another image. In addition, it would be useful to add a glossary of all the terms that one may find confusing such as “homologues”, “heterozygous”, “homology”, “notochord” etc. This in turn will provide the reader with enough information to understand the context of the project and in turn keep them engaged.<br />
<br />
Another negative aspect of the project was that the subheading “Ancient origins and evolution of the T-box gene family” randomly appearing nearing the end of the project. This looked a bit out of place and not flowing with the rest of the passage. To correct this it would be advised to add this to the start of the page with the “Origin of the T-box genes” section just so the information clearly flows from one topic to another without creating confusion. Overall, this project is coming along quite nicely. It is evident that a lot of research has been put into constructing a coherent and succinct project but also have the visual cues to back up the main aspects. To maximise marks, it is recommended to reflect on the feedback and correct the minor mistakes. <br />
<br />
<br />
<br />
Some searches to get us started:<br />
[http://www.ncbi.nlm.nih.gov/sites/gquery?term=t-box ''T-box'']<br />
[http://www.ncbi.nlm.nih.gov/sites/gquery?term=tbx ''tbx'']<br />
<br />
[[User:Z5020373|Z5020373]] ([[User talk:Z5020373|talk]]) 14:44, 26 August 2016 (AEST)<br />
PMID 25294936 - a relatively recent article that provides background info on the T-box gene family<br />
PMID 16285859<br />
<br />
[[User:Z3516832|Z3516832]] ([[User talk:Z3516832|talk]]) 14:52, 26 August 2016 (AEST)<br />
http://www.columbia.edu/itc/hs/medical/humandev/2007/HD15/HD15.pdf<br />
<br />
[[User:Z5020373|Z5020373]] ([[User talk:Z5020373|talk]]) 11:32, 16 September 2016 (AEST) Does anyone know how to draw up a table on the page? Thanks.</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2016_Group_Project_4&diff=249626
Talk:2016 Group Project 4
2016-10-06T16:35:18Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016discussionheader}}<br />
<br />
=Peer review=<br />
<br><br />
<br><br />
<u>Group 4:</u><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
<br />
Group 4 has provided numerous headings related to the Hedgehog pathway, such as its involvement in organ development, neural development as well as its mechanism of signalling during embryonic development (criteria 1). The group has also used an image of the signalling pathway to help provide a visual description of the different components of Hedgehog signalling (criteria 2). The authors of this project have also provided in-text citations for all information utilised and have also included a list of references at the end of their page (criteria 3). It is also evident that the group has investigated the involvement of the Shh signalling pathway outside of the scope of human embryonic development by exploring its role in mice, chicks and fruit flies, which is excellent (criteria 5 and 6). The authors have also began to include new research and abnormalities related to the Shh pathway (criteria 1).<br />
<br><br />
<br><br />
<br />
In order to further improve these positive aspects, the authors may provide a written description of the signalling pathway alongside the diagram utilised. This is because it is difficult to understand the signalling pathway just by looking at a diagram. Also, a suggestion would be to include a greater variety of diagrams and tables to support the descriptions already provided. Diagrams may relate to the animal models or the abnormalities described. A table may be utilised to summarise the history of the signalling pathway, such as different components of the pathway that were discovered and the year in which they were discovered. Additionally, whilst it appears that most of the information is correctly referenced, the authors have not correctly referenced the diagram that has been utilised to describe the signalling pathway, which is a breach of copyright laws. Therefore, a suggestion would be to ensure that all diagrams are referenced when added to the page.<br />
<br><br />
<br><br />
<br />
<b>Negative aspects of the project and suggested improvements: </b><br />
<br><br />
<br><br />
<br />
Whilst there were positive aspects to this project, a key negative aspect of the project is that the authors have not provided an introduction describing what the Hedgehog signalling pathway is. The introduction may include an overview of the nature and role of the hedgehog signalling pathway in embryonic development, thereby introducing headings in your page. It is also evident that the authors have not met criteria 2 completely, in that a small number of subheadings were utilised. Take for example the heading, “organogenesis”, no subheadings have been created under this heading. A suggested improvement would be to include subheadings relating to specific organs formed by the actions of the Shh pathway, accompanied by an in-depth description and diagrams. It is also evident that the authors utilise complex terminology within their description that often make it difficult to grasp certain concepts. Terms include “knockout”, “autocrine”, “appendage” and “paracrine” for example. A suggestion for improvement would be to include a table of glossary terms at the end of the page, defining these terms.<br />
<br><br />
<br><br />
It also appears that the authors have not provided a history regarding the Hedgehog signalling pathway and its discovery. A suggestion would be to include a timeline regarding the discovery of this signalling pathway, as it provides the audience with a background of how Shh came to be known. <br />
<br><br />
<br><br />
<br />
===Group 4===<br />
<br />
A good start has been made to the project with the appropriate selection of headings and subheadings which provide a brief overview of what is to be discussed in terms of the Hedgehog signalling pathway. By breaking down the mechanism of the pathway, it made the foreign concept much easier to understand. In saying this, this section is quite text-heavy and may benefit with the relocation of the included diagram or even inclusion of other diagrams and flowcharts to engage readers. With the introduction of a fairly new concept, the inclusion of visual or audio stimuli and maybe even a short quiz may encourage interaction with readers. <br />
<br />
The discussion of this pathway in mammals exposed readers to the diversity of the Hh signalling pathway but in saying this, the inclusion of a table may be useful to compare and contrast the differences between the pathways in mammals and insects. Overall, this section was well written. On the other hand, when considering the section on animal models, it provided insight into the role of Hh signalling pathway on embryological development and offered a brief introduction to the abnormalities caused by disruptions of this pathway. Once again, the inclusion of diagrams would be useful in this section to provide visual insight into the research being performed. <br />
<br />
Though there has been significant exploration of the mechanism and animal models utilised in this pathway, more work is needed to link this pathway to embryological development and this could provide a good leeway into understanding the abnormalities associated with disruption of this pathway. This project can be significantly improved simply by focusing on making it more interactive ad engaging with the inclusion of a variety of stimuli like tables, diagrams, quizzes and even videos. In addition, all information has been well cited and referenced and there has been substantial communication between group members, allowing team members to provide feedback and suggestions thus, ultimately increasing the quality of the work produced. <br />
<br />
<br />
===Group 4 – Hedgehog Pathway ===<br />
Positive aspects of this project include that Group 4 appear to have well defined subheadings, which function well to help the reader navigate through the page. The information is appropriately referenced using in-text citations, appearing to be from both primary and review articles. There is a significant amount of research on the mechanisms of the pathway but less of a focus on the role of this pathway in embryonic development, which I think is really important in order to relate it back to what we are leaning in both the lectures and tutorials. I think the inclusion of current research is a very important aspect to include in this project, as it identifies the current direction in which this research is heading. This might be also interesting to link to its clinical significance and abnormalities in the signaling pathway. <br />
<br />
However, some negative aspects of the page include the lack of an introduction as this essentially establishes your page. You need to include a brief outline of the signaling pathway, a summary of its role in development and the other aspects of it you are looking to discuss. Furthermore, the inclusion of an image outlining the signaling pathway without any information inducing or explaining it should be corrected. The project appears to be very informative but isn’t very interactive and lacks images. Perhaps sourcing images of results from some of the primary articles, which you have referenced or include videos outlining the signaling pathway, might be a useful addition. It might be a good idea to include a glossary at the bottom of the page to help readers to better understand some of these more difficult terms. Also under the subheading of history, like in some of the other projects, a table could be a useful addition, just summarizing all the scientific advances regarding this pathway since it was first discovered, this helps set up how far we have come and then may be helpful when talking about the direction in which we are heading under current research. <br />
<br />
In conclusion, this looks like it’s on its way to being a successful project. In summary though, a greater emphasis on its role in embryonic development and conscious effort to make the page more interactive and engaging for the reader will go a long way. <br />
<br />
<br />
===Group 4 Peer Assessment===<br />
<br />
Positive aspects of the project and improvements:<br />
<br />
At initial glance I can see a range of headings and subheadings which just made it easier to navigate from one aspect of the project to another. This satisfied the requirements for criteria 1 and 2. This also allowed me to recognise the main topic of the project is the Hedgehog signalling pathway. There is also an addition of an image of the pathway which was great to see as it outlines the main components of the pathway and in general educates the reader about the signalling pathway. This provided a visual stimulus/ description which in turn engaged the reader to find out more about the topic.<br />
<br />
It was also good to see correct in text citations and a references list at the end which in turn satisfied criteria 3. To satisfy criteria 5 it was excellent to see information that was well beyond the required information. An example of this is when discussing the role of the pathway in not only humans but also in mice, chicks and fruit flies. The group also began to include new research and abnormalities related to the Shh pathway which aided in rounding off criteria 1. <br />
<br />
In order to improve the already positives of this project it would be advised to add a description to the image just so the reader can have some sort of summary about the main points of the image/ pathway. Also, addition of diagrams or tables in some of the subheadings would be good as it will keep the reader interested and in general provide a visual aid. Also it is necessary to cite and provide a reference of the image as it breaches the copyright laws. <br />
<br />
Negative aspects of the project and improvements:<br />
<br />
Although there are positives to the project, there are a few negatives that can easily be fixed. It is crucial to put in an “Introduction” heading and providing relevant information. This in turn will create a coherent project as it flows from one aspect to another whilst simultaneously providing a brief overview of the Sonic Hedgehog Pathway. Although you have explored the mechanism in animal models it is imperative to link this to embryological development. Also, addition of diagrams, interactive quizzes and tables is necessary to satisfy criteria 3, since 1 image is not enough. <br />
<br />
Adding a glossary of terms at the end of the project is needed to clarify any words or phrases that have not been previously encountered such as “organogenesis”, “paracrine”, “dephosphorylation” etc. Overall, the project is coming along nicely and with the recommended amendments, a high mark is definitely in order. <br />
<br />
<br />
[[User:Z5019880|Z5019880]] ([[User talk:Z5019880|talk]]) 14:58, 26 August 2016 (AEST) Hey guys, I have added some sub-headings for the hedgehog signalling pathway, feel free to add any headings that might be useful for the topic, or suggest a different topic.<br />
<br />
Hey guys, I've started doing some research on the animal models for the Hedgehog signalling pathway. I'm currently finding it a little difficult understanding some of the terms when researching the experiments done on Drosophila melanogaster so I was wondering if you had any suggestions as to how much detail to include. Also I have included some links that maybe useful for those researching mechanism and history:<br />
<ref><pubmed>17925578</pubmed></ref><br />
<ref><pubmed>26839340</pubmed></ref><br />
<br />
Also, I thought I would just put in writing here that we want everyone to have completed their parts by the end of mid semester break so that we can meet up the following week to fix any issues with formatting and work on the introduction, conclusion etc. Thanks guys!! <br />
P.S. Did Mark mention that we shouldn't use research articles?<br />
<br />
[[User:Z5019880|Z5019880]] ([[User talk:Z5019880|talk]]) 23:30, 12 September 2016 (AEST) Hey, what you have added is really good! To be honest I'm not completely sure about how technical we have to be, because I have also found my self that there is a lot of chemistry when it comes to the signalling pathways etc. which makes it incredibly difficult for me to understand. At this point I reckon what you have now is enough, but we can always revisit it when we have added more to the page, to keep the content at a consistent depth. Also with regards to the research articles, I'm not entirely sure what Mark said, but I'm sure it would be alright to see what is written, and click into the citations to get further information, and just cite that. Anyway I've added a small piece on the processing of the Hh protein, but am unsure if It would be necessary to go more into the chemistry behind how the auto-cleavage occurs.<br />
<br />
So I've read what you have written and I think it sounds coherent and it's also very easy to understand so good job! I think I'll do a little more research, I think it might be a little tedious to add information of Shh knockout mice considering the experiments on the chick embryo were quite similar but I'm open to suggestions. I was also thinking it would be useful to include a link to a short youtube video of some sort that would be able to visually explain the Hh signalling pathway (something like this https://www.youtube.com/watch?v=w1xXD9kss2w but unfortunately this video has no audio but has some good visual and written cues). In regards to an image, I actually found a pretty decent image of this pathway but I'm not too sure if we can use it due to copyright. It says we can if it's not for commercial use so I think we should be ok.<br />
<br />
Please let me know what you think of the diagram. I've just added something that looks like it could be helpful but feel free to edit/remove it if you don't think it is appropriate :)<br />
<br />
[[User:Z5019880|Z5019880]] ([[User talk:Z5019880|talk]]) 22:28, 26 September 2016 (AEST) The diagram looks great! I reckon as long as we include all the copyright it should be fine. We can probably eventually move the image next to the mechanism of signalling section when it is finished. I have started it, and will continue finishing it tomorrow, so if there are any issues with how I'm going about it, please don't hesitate to tell me.<br />
<br />
Good idea! I've added some information on Shh Knockout mice so any feedback on what I have written will be greatly appreciated! I'm also thinking of looking into videos that we could link as part of our assignment to make the concept easier to understand.<br />
<br />
[[User:Z5019880|Z5019880]] ([[User talk:Z5019880|talk]]) 21:30, 28 September 2016 (AEST) Hey, I've read your section on Shh and it seems good. In terms of what you could add, do you reckon it is appropriate to talk about the advantage of using each of the models over one another, and possible problems you might encounter with each model. I get that it's probably hard to find material on that, so don't worry if that's the case. Also a video would be a great idea, although we should first check with Mark with regards to what sources would be appropriate. Anyway I have finished the first part of the mechanism part regarding the general pathway for Hh proteins that have specifically been studied in the fruit fly, and will continue onto vertebrates later. I was wondering from what you guys have studied on this pathway if I have covered most of the areas sufficiently and in a coherent matter. Any other feedback is also appreciated.<br />
<br />
I've read what you've written and you've successfully made it really easy to understand. From the knowledge I've gained through reading articles on this pathway, I don't think you have missed anything thus far. The only improvement I could suggest is maybe referencing an image in your explanation so that readers have a visual stimulus to refer to to ease understanding of the pathway. In regards to looking at the differences between the models, I genuinely tried to find a comparison between the animal models but was met with no such information unfortunately. I'll try and have a look sometime soon. Also, I was thinking maybe we could include a quiz of some sort to make our project more interactive. We could do this by adding a quiz after each section or just one quiz at the very end. Our project is also quite text heavy so I think we should find more images and other stimuli to make it more interesting. We should create a timeline of events for the history of the pathway in the form of a table. Also, should we create a glossary?<br />
<br />
Also, quick question, who's handling history, function and current research?</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2016_Group_Project_4&diff=249624
Talk:2016 Group Project 4
2016-10-06T16:34:48Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016discussionheader}}<br />
<br />
=Peer review=<br />
<br><br />
<br><br />
<u>Group 4:</u><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
<br />
Group 4 has provided numerous headings related to the Hedgehog pathway, such as its involvement in organ development, neural development as well as its mechanism of signalling during embryonic development (criteria 1). The group has also used an image of the signalling pathway to help provide a visual description of the different components of Hedgehog signalling (criteria 2). The authors of this project have also provided in-text citations for all information utilised and have also included a list of references at the end of their page (criteria 3). It is also evident that the group has investigated the involvement of the Shh signalling pathway outside of the scope of human embryonic development by exploring its role in mice, chicks and fruit flies, which is excellent (criteria 5 and 6). The authors have also began to include new research and abnormalities related to the Shh pathway (criteria 1).<br />
<br><br />
<br><br />
<br />
In order to further improve these positive aspects, the authors may provide a written description of the signalling pathway alongside the diagram utilised. This is because it is difficult to understand the signalling pathway just by looking at a diagram. Also, a suggestion would be to include a greater variety of diagrams and tables to support the descriptions already provided. Diagrams may relate to the animal models or the abnormalities described. A table may be utilised to summarise the history of the signalling pathway, such as different components of the pathway that were discovered and the year in which they were discovered. Additionally, whilst it appears that most of the information is correctly referenced, the authors have not correctly referenced the diagram that has been utilised to describe the signalling pathway, which is a breach of copyright laws. Therefore, a suggestion would be to ensure that all diagrams are referenced when added to the page.<br />
<br><br />
<br><br />
<br />
<b>Negative aspects of the project and suggested improvements: </b><br />
<br><br />
<br><br />
<br />
Whilst there were positive aspects to this project, a key negative aspect of the project is that the authors have not provided an introduction describing what the Hedgehog signalling pathway is. The introduction may include an overview of the nature and role of the hedgehog signalling pathway in embryonic development, thereby introducing headings in your page. It is also evident that the authors have not met criteria 2 completely, in that a small number of subheadings were utilised. Take for example the heading, “organogenesis”, no subheadings have been created under this heading. A suggested improvement would be to include subheadings relating to specific organs formed by the actions of the Shh pathway, accompanied by an in-depth description and diagrams. It is also evident that the authors utilise complex terminology within their description that often make it difficult to grasp certain concepts. Terms include “knockout”, “autocrine”, “appendage” and “paracrine” for example. A suggestion for improvement would be to include a table of glossary terms at the end of the page, defining these terms.<br />
<br><br />
<br><br />
It also appears that the authors have not provided a history regarding the Hedgehog signalling pathway and its discovery. A suggestion would be to include a timeline regarding the discovery of this signalling pathway, as it provides the audience with a background of how Shh came to be known. <br />
<br><br />
<br><br />
<br />
===Group 4===<br />
<br />
A good start has been made to the project with the appropriate selection of headings and subheadings which provide a brief overview of what is to be discussed in terms of the Hedgehog signalling pathway. By breaking down the mechanism of the pathway, it made the foreign concept much easier to understand. In saying this, this section is quite text-heavy and may benefit with the relocation of the included diagram or even inclusion of other diagrams and flowcharts to engage readers. With the introduction of a fairly new concept, the inclusion of visual or audio stimuli and maybe even a short quiz may encourage interaction with readers. <br />
<br />
The discussion of this pathway in mammals exposed readers to the diversity of the Hh signalling pathway but in saying this, the inclusion of a table may be useful to compare and contrast the differences between the pathways in mammals and insects. Overall, this section was well written. On the other hand, when considering the section on animal models, it provided insight into the role of Hh signalling pathway on embryological development and offered a brief introduction to the abnormalities caused by disruptions of this pathway. Once again, the inclusion of diagrams would be useful in this section to provide visual insight into the research being performed. <br />
<br />
Though there has been significant exploration of the mechanism and animal models utilised in this pathway, more work is needed to link this pathway to embryological development and this could provide a good leeway into understanding the abnormalities associated with disruption of this pathway. This project can be significantly improved simply by focusing on making it more interactive ad engaging with the inclusion of a variety of stimuli like tables, diagrams, quizzes and even videos. In addition, all information has been well cited and referenced and there has been substantial communication between group members, allowing team members to provide feedback and suggestions thus, ultimately increasing the quality of the work produced. <br />
<br />
<br />
===Group 4 – Hedgehog Pathway ===<br />
Positive aspects of this project include that Group 4 appear to have well defined subheadings, which function well to help the reader navigate through the page. The information is appropriately referenced using in-text citations, appearing to be from both primary and review articles. There is a significant amount of research on the mechanisms of the pathway but less of a focus on the role of this pathway in embryonic development, which I think is really important in order to relate it back to what we are leaning in both the lectures and tutorials. I think the inclusion of current research is a very important aspect to include in this project, as it identifies the current direction in which this research is heading. This might be also interesting to link to its clinical significance and abnormalities in the signaling pathway. <br />
<br />
However, some negative aspects of the page include the lack of an introduction as this essentially establishes your page. You need to include a brief outline of the signaling pathway, a summary of its role in development and the other aspects of it you are looking to discuss. Furthermore, the inclusion of an image outlining the signaling pathway without any information inducing or explaining it should be corrected. The project appears to be very informative but isn’t very interactive and lacks images. Perhaps sourcing images of results from some of the primary articles, which you have referenced or include videos outlining the signaling pathway, might be a useful addition. It might be a good idea to include a glossary at the bottom of the page to help readers to better understand some of these more difficult terms. Also under the subheading of history, like in some of the other projects, a table could be a useful addition, just summarizing all the scientific advances regarding this pathway since it was first discovered, this helps set up how far we have come and then may be helpful when talking about the direction in which we are heading under current research. <br />
<br />
In conclusion, this looks like it’s on its way to being a successful project. In summary though, a greater emphasis on its role in embryonic development and conscious effort to make the page more interactive and engaging for the reader will go a long way. <br />
<br />
<br />
===Group 4 Peer Assessment===<br />
<br />
Positive aspects of the project and improvements:<br />
<br />
At initial glance I can see a range of headings and subheadings which just made it easier to navigate from one aspect of the project to another. This satisfied the requirements for criteria 1 and 2. This also allowed me to recognise the main topic of the project is the Hedgehog signalling pathway. There is also an addition of an image of the pathway which was great to see as it outlines the main components of the pathway and in general educates the reader about the signalling pathway. This provided a visual stimulus/ description which in turn engaged the reader to find out more about the topic.<br />
<br />
It was also good to see correct in text citations and a references list at the end which in turn satisfied criteria 3. To satisfy criteria 5 it was excellent to see information that was well beyond the required information. An example of this is when discussing the role of the pathway in not only humans but also in mice, chicks and fruit flies. The group also began to include new research and abnormalities related to the Shh pathway which aided in rounding off criteria 1. <br />
<br />
In order to improve the already positives of this project it would be advised to add a description to the image just so the reader can have some sort of summary about the main points of the image/ pathway. Also, addition of diagrams or tables in some of the subheadings would be good as it will keep the reader interested and in general provide a visual aid. Also it is necessary to cite and provide a reference of the image as it breaches the copyright laws. <br />
<br />
Negative aspects of the project and improvements:<br />
<br />
Although there are positives to the project, there are a few negatives that can easily be fixed. It is crucial to put in an “Introduction” heading and providing relevant information. This in turn will create a coherent project as it flows from one aspect to another whilst simultaneously providing a brief overview of the Sonic Hedgehog Pathway. Although you have explored the mechanism in animal models it is imperative to link this to embryological development. Also, addition of diagrams, interactive quizzes and tables is necessary to satisfy criteria 3, since 1 image is not enough. <br />
<br />
Adding a glossary of terms at the end of the project is needed to clarify any words or phrases that have not been previously encountered such as “organogenesis”, “paracrine”, “dephosphorylation” etc. Overall, the project is coming along nicely and with the recommended amendments, a high mark is definitely in order. <br />
<br />
<br />
[[User:Z5019880|Z5019880]] ([[User talk:Z5019880|talk]]) 14:58, 26 August 2016 (AEST) Hey guys, I have added some sub-headings for the hedgehog signalling pathway, feel free to add any headings that might be useful for the topic, or suggest a different topic.<br />
<br />
Hey guys, I've started doing some research on the animal models for the Hedgehog signalling pathway. I'm currently finding it a little difficult understanding some of the terms when researching the experiments done on Drosophila melanogaster so I was wondering if you had any suggestions as to how much detail to include. Also I have included some links that maybe useful for those researching mechanism and history:<br />
<ref><pubmed>17925578</pubmed></ref><br />
<ref><pubmed>26839340</pubmed></ref><br />
<br />
Also, I thought I would just put in writing here that we want everyone to have completed their parts by the end of mid semester break so that we can meet up the following week to fix any issues with formatting and work on the introduction, conclusion etc. Thanks guys!! <br />
P.S. Did Mark mention that we shouldn't use research articles?<br />
<br />
[[User:Z5019880|Z5019880]] ([[User talk:Z5019880|talk]]) 23:30, 12 September 2016 (AEST) Hey, what you have added is really good! To be honest I'm not completely sure about how technical we have to be, because I have also found my self that there is a lot of chemistry when it comes to the signalling pathways etc. which makes it incredibly difficult for me to understand. At this point I reckon what you have now is enough, but we can always revisit it when we have added more to the page, to keep the content at a consistent depth. Also with regards to the research articles, I'm not entirely sure what Mark said, but I'm sure it would be alright to see what is written, and click into the citations to get further information, and just cite that. Anyway I've added a small piece on the processing of the Hh protein, but am unsure if It would be necessary to go more into the chemistry behind how the auto-cleavage occurs.<br />
<br />
So I've read what you have written and I think it sounds coherent and it's also very easy to understand so good job! I think I'll do a little more research, I think it might be a little tedious to add information of Shh knockout mice considering the experiments on the chick embryo were quite similar but I'm open to suggestions. I was also thinking it would be useful to include a link to a short youtube video of some sort that would be able to visually explain the Hh signalling pathway (something like this https://www.youtube.com/watch?v=w1xXD9kss2w but unfortunately this video has no audio but has some good visual and written cues). In regards to an image, I actually found a pretty decent image of this pathway but I'm not too sure if we can use it due to copyright. It says we can if it's not for commercial use so I think we should be ok.<br />
<br />
Please let me know what you think of the diagram. I've just added something that looks like it could be helpful but feel free to edit/remove it if you don't think it is appropriate :)<br />
<br />
[[User:Z5019880|Z5019880]] ([[User talk:Z5019880|talk]]) 22:28, 26 September 2016 (AEST) The diagram looks great! I reckon as long as we include all the copyright it should be fine. We can probably eventually move the image next to the mechanism of signalling section when it is finished. I have started it, and will continue finishing it tomorrow, so if there are any issues with how I'm going about it, please don't hesitate to tell me.<br />
<br />
Good idea! I've added some information on Shh Knockout mice so any feedback on what I have written will be greatly appreciated! I'm also thinking of looking into videos that we could link as part of our assignment to make the concept easier to understand.<br />
<br />
[[User:Z5019880|Z5019880]] ([[User talk:Z5019880|talk]]) 21:30, 28 September 2016 (AEST) Hey, I've read your section on Shh and it seems good. In terms of what you could add, do you reckon it is appropriate to talk about the advantage of using each of the models over one another, and possible problems you might encounter with each model. I get that it's probably hard to find material on that, so don't worry if that's the case. Also a video would be a great idea, although we should first check with Mark with regards to what sources would be appropriate. Anyway I have finished the first part of the mechanism part regarding the general pathway for Hh proteins that have specifically been studied in the fruit fly, and will continue onto vertebrates later. I was wondering from what you guys have studied on this pathway if I have covered most of the areas sufficiently and in a coherent matter. Any other feedback is also appreciated.<br />
<br />
I've read what you've written and you've successfully made it really easy to understand. From the knowledge I've gained through reading articles on this pathway, I don't think you have missed anything thus far. The only improvement I could suggest is maybe referencing an image in your explanation so that readers have a visual stimulus to refer to to ease understanding of the pathway. In regards to looking at the differences between the models, I genuinely tried to find a comparison between the animal models but was met with no such information unfortunately. I'll try and have a look sometime soon. Also, I was thinking maybe we could include a quiz of some sort to make our project more interactive. We could do this by adding a quiz after each section or just one quiz at the very end. Our project is also quite text heavy so I think we should find more images and other stimuli to make it more interesting. We should create a timeline of events for the history of the pathway in the form of a table. Also, should we create a glossary?<br />
<br />
Also, quick question, who's handling history, function and current research?</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2016_Group_Project_3&diff=249622
Talk:2016 Group Project 3
2016-10-06T16:33:19Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016discussionheader}}<br />
<br />
==Peer Review==<br />
<br />
===Group 3===<br />
<br />
You guys have made a good start on your project! I particularly liked how the headings were subdivided appropriately into smaller subheadings as it effectively broke down the FGFR pathway and made the page easy to navigate. Though you have included a short and succinct introduction, I think it should address all the sections being discussed to give the reader a better overview of your project. In addition, the use of a table to explore the timeline of research of the FGF pathway was an excellent idea but I think the text above the table could be incorporated into the table itself and a more extensive timeline could be provided. <br />
<br />
Though it was good that you provided a brief overview of the FGFR pathway, you’ve only discussed the components of the pathway rather than the pathway itself. Furthermore, when discussing signal transduction, I think you should be more specific when explaining the process, for example when you mentioned ‘which leads to changes in gene transcription through interactions with DNA’, it causes changes in transcription in which genes and through interactions with which DNA? In saying this, it was wonderful to see the inclusion of a hand-drawn diagram which represents not only your understanding of the pathway but also aids readers understanding of the FGFR pathway. <br />
<br />
A good overview has been provided to explain the role of FGFs in embryonic development. The only suggestion I can make is to provide explanations or full names of the abbreviations to aid understanding of the concepts explored. For example, what is ETV1 and EWSR1? By explaining what these abbreviations are the reader will gain better understanding on how they function to help maintain FGF10 expression. In terms of the section on abnormalities, a succinct and coherent introduction was provided. There was a good description of the morphological changes produced by these mutations along with the cause of these abnormalities. There isn’t much I would change in this section except for maybe explaining FGFR2 mutation. <br />
<br />
Overall, you guys have done a fantastic job! I thought the inclusion of a quiz was particularly innovative as it makes your project interactive and thus, aids the learning process. Everything was well cited and referenced and it was wonderful to see the use of an original diagram. It was also good to see all groups members contributing to the discussion page which indicates effective communication within the team. <br />
<br />
===Group 3 Critical Assessment===<br />
A great introduction to the topic, allowing the reader to slowly transition into the more in-depth points! I particularly like how you have broken down the different constituents of the pathway such as the receptors and protein subtypes and provided a succinct table outlining their function and clinical significance before moving onto the mechanism. Although the ‘FGF Subtype’ table has proven to be effective and helpful, the table on ‘History’ does not seem to be thorough and is very limited. Possibly extending the table by researching more developments in the field of FGF Signalling could make it appear more complete. <br />
<br />
Effort has been made to include a hand drawn image of the signalling pathway, which serves as a great source of aid in understanding how the pathway works whilst reading the text beside it. In saying that, effort should be further made to include a complete glossary and ensure terms such as ‘receptor dimerization’ ‘morphogenesis’ are broken down for the reader in order to satisfy criteria 4. This is not only seen in the ‘Signal Transduction’ section but also throughout the other sections. As you have included a fantastic image on bone development to represent the information visually, it would also be a good idea to post up images covering the other areas of embryonic development, such as kidney and inner ear development! You could even consider including short clips explaining these processes to make the page more interactive. <br />
<br />
It is clear a decision has been made to talk about ‘Animal Models’. As well as including text on the topic, a possible option could be including a table briefly outlining which animal model has contributed to what knowledge in relation to the pathway in order to simplify the information. <br />
<br />
A particular highlight of the Wiki page is the use of a quiz. It is great to see viewers can test their understanding of the topic towards the end and challenge themselves! For the correct option to each question a link to a supporting article or particular section of the page can be provided so the viewer can revisit the information should they have answered the question incorrectly. Overall a great use of tables, images and interactive components!<br />
<br />
===Group 3 Peer Assessment=== <br />
<br />
With regards to your project I have noticed there are many forms of educational tools employed or being planned other than text, which to me is a big plus with regards to your project. The usage of the table to summarises the different FGFR sub-types is really easy to read and understand, and presents the information in a better way than you could’ve with just a wall of text. Your planned multiple choice section seems like it would be a nice addition to your page where it should help solidify the knowledge of the reader, allowing to check what they know. When doing the quiz section not only would it be good if you added explanations for the correct answers, but maybe also if possible explanations of why the other answers are wrong. There seems to be no issues with your citations given that all of them are in-text and multiple. Also the link between signal transduction, embryonic development and abnormalities is quite smooth and within context of their respective preceding parts, making the page read very well. <br />
<br />
With regards to your usage of images, it seems mostly good and compliments the passages well, but I feel that it would benefit with adding more information to the legend, possibly by moving some of the description when clicking into the image into the legend. Also since your first image contains mainly abbreviations, maybe it would be good to collate all abbreviations and add it to the glossary such that the reader can easily refer to what the abbreviations mean. <br />
<br />
With respect to your signal transduction section, all the components of the pathway seem to have been included, but for the most part how each factor interacts with one another has been left out. Elaborating on how each factor interacts and activates one another such as how FRS2 recruits GRB2 and SHP2, and how those events actually promote activation of RAS. I feel adding this will really improve the depth of this section, and make it less about a bunch of different components and more about how the work together in the context of their individual functions. Also I feel that the history section could be expanded on, maybe to include more time points or critical areas of discovery for the FGFR pathway.<br />
<br />
Overall I think your project is shaping up quite well, and that with the addition of the suggestions made above, would make your project quite good. Having used many images, a table, and including the quiz has really made your page quite interactive and engaging which has really benefited your page. Also your subheadings and included passages have appeared to cover most important topics within your signalling pathway. <br />
<br />
<br />
===Group 3 Peer Assessment=== <br />
Positive aspects of the project and improvements:<br />
<br />
The group project looks terrific at the initial glance. You can clearly see all the headings and subheadings. In particular, it is great to see a range of subheadings such as “limb bud formation”, “bone development”, “kidney development”. This shows that there was a lot of research put into this project. Also by doing so you have made it clear that your project is about the Fibroblast Growth Factor Receptor Pathway (FGFR). The page is also very easy to navigate as well which was nice to see. <br />
It is also great to see that there is addition of tables, images, and diagrams as it kept the read a lot more interesting and captivating. This allowed you to successfully satisfy criteria 2. It is also good to see correct in text citations and references as this allowed the reader to search for additional information if interested or necessary. Although you haven’t made up any multiple choice questions it is excellent to see a MCQ section. This is a great way to test the readers’ knowledge and in turn you can reflect if you have provided accurate and sufficient information to answer these questions. <br />
<br />
It was great to see that you added an abnormalities section and in particular different types of syndromes and disorders. This meant that you went over the minimum information required and put in extra effort to create a coherent project. This satisfied criteria 5 and thus a better project. Overall there are many positives in this report and with minor amendments such as adding information to sections such as “Apert syndrome”, “Animal models”, “Kidney development”, “external genitalia development” etc, a very articulate and well rounded project will be created.<br />
<br />
Negative aspects of the project and improvements:<br />
<br />
Although there are many positives in the project, there should be some amendments to the project just to ensure all bases are covered. Firstly, it would be advised to increase the amount of information to the introduction and history sections. As these sections are lacking information, the reader may not have enough information to carry on reading as their base on this topic isn’t really strong and lacks information. This can easily turn off new readers and inhibit further exploration of the topic/ project. By adding additional dates in the history section, a better overall knowledge and background of the signalling pathway can be developed which can only enhance learning. <br />
<br />
Overall, there are not many negatives and I believe as a reader your project was a great example of progress so far and with the aforementioned minor tweaks, your group is well on their way to achieving extremely high marks. <br />
<br />
<br />
<br />
==<u><font size="4.5">Comments by Group 3</font></u>==<br />
[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 12:36, 19 August 2016 (AEST) I thought looking into how prenatal cannabis exposure influences signalling during development might be interesting<br />
<br />
[[User:Z5017002|Z5017002]] ([[User talk:Z5017002|talk]]) 12:47, 19 August 2016 (AEST) Ooh cool idea, I agree that looks really interesting, there seems to be a lot of literature about its influence on brain development<br />
<br />
[[User:Z5015544|Z5015544]] ([[User talk:Z5015544|talk]])z5015544[[User:Z5015544|Z5015544]] ([[User talk:Z5015544|talk]]) Thats excellent, what about the sonic hedgehog pathway?<br />
<br />
[[User:Z5015544|Z5015544]] ([[User talk:Z5015544|talk]])Other ideas[[User:Z5015544|Z5015544]] ([[User talk:Z5015544|talk]]) WNT Signaling Pathway is another one to look at<br />
<br />
How can we harvest stem cells from the embyro for use in later life - z5015337<br />
<br />
[[User:Z5015544|Z5015544]] ([[User talk:Z5015544|talk]])z5015544[[User:Z5015544|Z5015544]] ([[User talk:Z5015544|talk]]) Ok guys I created a couple of subheadings and provided a brief history. Make sure to use primary research articles that are peer-reviewed because I just spoke to Dr Hill and noticed he stressed that a lot.<br />
<br />
[[User:Z5015337|Z5015337]] ([[User talk:Z5015337|talk]]) I have scoured through the projects of old to get a better idea about what is expected from us for this project - [[User:Z5015337|Z5015337]] ([[User talk:Z5015337|talk]])<br />
<br />
[[User:Z5015337|Z5015337]] ([[User talk:Z5015337|talk]])I found this giant slab of text regarding the structures of the receptors involved from a journal article and I am working through culling it down for a usable structure definition: FGF receptors and FGF signal transduction. FGFRs are modular proteins comprising 3 immunoglobulin domains (IgI, IgII and IgIII). IgI and IgII are separated by an acidic box (AD). IgII contains a heparin binding domain (HBD). The IgIII domain is followed by a unique transmembrane (TM), a juxtamembrane (JM) and a kinase domain (KD) interrupted by an interkinase domain (IKD). FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to IgII and IgIII of FGFR. This results in the dimerization and the subsequent transactivation by phosphorylation of specific tyrosine residues. The main two transduction pathways involve the phospholipase C-γ (PLCγ) and the Ras/MAP kinase. The SH2 domain of the PLCγ interacts with the phosphorylated Y766 of the activated receptor. The activated PLCγ hydrolyzes the phosphatidyl-inositol-4,5-diphosphate (PIP2) to inositol-1,4,5-triphophate (IP3) and the diacylglycerol (DAG). IP3 releases Ca2+ while DAG activates the protein kinase C-δ (PKCδ). Activated PKCδ activates Raf by phosphorylating its S338 and stimulates the downstream pathway in a Ras independent manner. The main pathway involves the interaction of the docking protein FRS2α with the amino-acid residues 407–433 (Xu et al., 1998). This protein is activated by phosphorylation on multiple tyrosine residues and subsequently interacts and activates Grb2 linked to Sos, a nucleotide exchange factor involved in the activation of Ras. Activated Ras then activates Raf which stimulates MEK which in turn phosphorylates the MAP kinase ERK. This last activated component translocates to the nucleus and phosphorylates specific transcription factors of the Ets family which in turn activate expression of specific FGF target genes. P: phosphorylation<br />
<br />
[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 18:31, 14 September 2016 (AEST) Hey guys I've just changed our subheadings so we can better allocate something for each of us to write on this week. More then happy to change them! Just came across these while I was researching. Did everyone maybe want to put their name next to something they are able to research or chuck in new subheadings that interest them?<br />
<br />
[[User:Z5015544|Z5015544]] ([[User talk:Z5015544|talk]]) 14:31, 16 September 2016 (AEST)Hey guys, here is the link for omim. Type in the name of the gene and it will give you different articles about it: http://www.omim.org/[[User:Z5015544|Z5015544]] ([[User talk:Z5015544|talk]]) 14:31, 16 September 2016 (AEST)<br />
<br />
[[User:Z5015544|Z5015544]] ([[User talk:Z5015544|talk]]) 14:41, 16 September 2016 (AEST)Things to include: Flow diagram of the FGFR pathway, 3D diagram of the FGF protein (can be hand-drawn)[[User:Z5015544|Z5015544]] ([[User talk:Z5015544|talk]]) 14:41, 16 September 2016 (AEST)<br />
<br />
[[User:Z5015544|Z5015544]] ([[User talk:Z5015544|talk]]) 23:22, 28 September 2016 (AEST)Hey guys, hope you're all enjoying the break. Just thought I would let you know I've added a hand drawn diagram and a table too. If anyone finds more information about specific receptor functions in embryo development please add it to the table.[[User:Z5015544|Z5015544]] ([[User talk:Z5015544|talk]]) 23:22, 28 September 2016 (AEST)<br />
<br />
[[User:Z5015686|Z5015686]] ([[User talk:Z5015686|talk]]) 12:35, 29 September 2016 (AEST) '''just moved this from our main page''' Extra Resources<br />
Useful review articles that may be worth a read through: <br />
http://onlinelibrary.wiley.com/doi/10.1002/wdev.176/full<br />
http://www.nature.com.wwwproxy0.library.unsw.edu.au/nrd/journal/v8/n3/pdf/nrd2792.pdf <br />
http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0012160605006184<br />
http://www.nature.com.wwwproxy0.library.unsw.edu.au/nrm/journal/v14/n3/full/nrm3528.html<br />
http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1002/jcp.24649/full <br />
http://genesdev.cshlp.org/content/29/14/1463.full (FGF signalling and skeletogenesis, specifically how mutations to the FGF signalling pathway may be responsible for skeletal diseases)<br />
<br />
[[User:Z5015544|Z5015544]] ([[User talk:Z5015544|talk]]) 01:14, 4 October 2016 (AEDT)Looking really good guys, I think we should try and expand beyond what has been covered in the lectures. Maybe we can look at new research involving FGF. We can also look at FGF in animals and how it affects limb development. Let me know what you guys think</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2016_Group_Project_1&diff=249620
Talk:2016 Group Project 1
2016-10-06T16:31:27Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016discussionheader}}<br />
=Peer Review=<br />
<font size="4"><u>Group 1:</u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br><br />
Upon assessment of this project, it appears that the authors have devised a variety of subheadings related to the signalling pathway of the Wnt receptor in embryonic development which is excellent. The group has also began investigating the involvement of Wnt in numerous aspects of embryonic development such as skin formation. The use of subheadings and headings related to the Wnt receptor partially meets criteria 1 and 2 assessment. It also appears that the group has cited and referenced sources for some of the information utilised, particularly when describing the “Caronical Pathway”. This also partially meets criteria 3 for this assessment. The group has also attempted to explore abnormalities in the Wnt pathway by describing interruptions in the pathway and its relation to cancer which is very interesting. They have therefore attempted to research ideas related to this receptor that extend beyond formal teaching activities, by explaining the link between Wnt abnormalities and disease (criteria 5). <br />
<br><br />
<br><br />
Whilst there are the positive aspects of the page, improvements can still be made to ensure that the group satisfies the first five points of the marking criteria. Firstly, although there appears to be subheadings, there only appear to be few and therefore it would be excellent to add more subheadings. Subheadings may relate to the history of the Wnt signalling pathway or even subtypes of the receptor as well as their respective functions. In addition, whilst the group appear to have cited some of their sources, it is important to cite all sources, particularly when gathering data under the “Non-canonical pathway” subheading. Although a series of articles have been referred to, it is vital that the group includes in-text citations in order for the audience to determine the source for each segment of information. A suggestion would be to investigate more examples of diseases caused by abnormalities in the Wnt signalling pathway<br />
<br><br />
<br><br />
<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
The group appeared to provide a general description of the abnormalities associated with disruption of the Wnt pathway; however they did not talk about abnormalities in the context of embryonic development. A suggestion would be to discuss Wnt abnormalities to the effect it has on embryonic development. It was also noticed that the group failed to include diagrams, tables or figures to reinforce the information. The use of diagrams would assist the audience in developing a visual understanding of the information presented and also makes the wiki page more appealing too. Therefore, a suggestion would be to use diagrams and figures. For example, a diagram of the signalling pathway would be a suggestion. It was noticed that the page appears to have no introduction or history describing the Wnt receptor. Therefore, a possible improvement would be to include a brief introduction and history at the beginning of the page as well as a few diagrams to provide the audience with an insight into what the receptor’s purpose is before exploring its function in embryonic developing.<br />
<br><br />
<br><br />
In addition, it appears that the group has focused on the role of Wnt in skin development of the embryo only. A possible improvement would be to investigate the involvement of Wnt in other areas of embryonic development, perhaps the development of specific organ systems or other structures.<br />
<br><br />
<br><br />
<br><br />
<br><br />
<br><br />
<br><br />
To all group members:<br />
*More info on pathway focusing on fetus development, and which pathway it is majorly part of - focus research on those body parts<br />
*Make your section presentable<br />
*At least one picture per section<br />
<br />
===Group 1===<br />
<br />
You guys have made significant progress on your project, managing to touch briefly on each section of your assignment. There have been some good choices of subheadings but I think some improvement can be made. For example, I think it would be useful to breakdown the general heading of ‘introduction’ into smaller subheadings so readers are made aware of what will be discussed in this section. It would also be useful to touch upon the importance of this pathway and thus, highlighting its significance in embryological development. <br />
<br />
In terms of the content of the project, being only in the draft stage a considerable amount of editing is required. For example, there has been mention of the TCF/LEF family and though the use of this abbreviations is useful, I think it would be appropriate to initially include the full name and explain this term in brief detail. In addition, there has been discussion of the ‘canonical’ and ‘non-canonical’ pathways of WnT Signalling Pathway but you could consider discussing the significance of having these two separate pathways. Comparing and contrasting these two pathways may also assist in aiding one’s understanding of the topic. <br />
<br />
Though it is great that you have made progress, I think more detail is required in each section, particularly in linking the effect of these pathways on embryological development. Also, greater attention needs to paid to referencing and utilisation of studies that have dissected this signalling pathway. For example, greater emphasis can be placed on studies performed on ‘embryos of Xenopus laevis’ or the in vitro experiments on mice. Instead of saying ‘a study’ or ‘another study’ acknowledge the researchers of this study as it will increase the validity of your argument while providing readers with the opportunity to refer back to these papers for more information if required or interested. More detail is also required on the effect of this pathway on skin formation. One way this could be done is by expanding on the information already provided, for example, explain how ‘WnT signalling inhibits the ectoderm’s responsiveness to FGFs’ and provide a detailed explanation of the feedback mechanism. Though your topic is focusing on ‘WnT Signalling pathway in the skin of fetus’ It would be beneficial to explore the roles of Wnt signalling in other areas of embryological development as this could provide insight into the abnormalities caused by mutations in this pathway. In terms of the ‘what can go wrong’ section, try breaking this segment into the various embryological deficiencies that can develop through disruption of the WnT pathway and try and make it relevant by providing statistics. <br />
<br />
Overall, you guys have done a fantastic job! It was good to see that all group members had contributed to the project. The main thing that requires improvement is the lack of detail. Through editing and inclusion of appropriate references and citations you can significantly improve the quality of your work. It would be useful to add some diagrams or images to help explain the pathway. In addition, try utilising your discussion page and communicating with your other team members. By providing feedback and suggestions you can assist in efficiently producing an excellent project. I hope this helps!! <br />
<br />
===Group 1 Critical Assessment===<br />
In terms of the topic of WnT signalling pathway, the page is beginning to come together with a great amount of information. What I particularly like is how the different concepts introduced in the page have been explained, for e.g. the different WnT pathways. However the content for each pathway does not seem to be consistent. While the canonical pathway addresses the mechanism, the non-canonical one doesn’t. I would suggest constructing a table to compare the similarities and differences between the various pathways, and adding images or shorts clips with audio to represent the elements of the pathways in a different form. This would not only enhance the look of your page but also make it more interactive for the audience. <br />
<br />
A great positive is to see links to research articles have been provided for the audience to access if they are interested to read on further. The links are short and easy to see, and direct you straight to the article on Pubmed, a reliable source. An effort has also been made to summarise the article, however the summary should be available as a simple breakdown so the audience can refer to it if they struggle to understand. The summaries include some jargon that can be further simplified. <br />
<br />
In relation to criteria 1, the key points have definitely been highlighted and the signalling pathway has been associated with the fetal development, however to make it more interesting and satisfy criteria 5, possibly construct a table or briefly outline how WnT signalling is involved in other areas such as Type 2 Diabetes and Cancer. Furthermore, to relate the topic back to embryological development explore the pathway in other areas such as gastrulation, rather than limiting discussion to skin development.<br />
<br />
Lastly to satisfy criteria 3, attempt to include in text citations within the paragraphs, instead of displaying references towards the end of the page. Overall, great job in gathering and highlighting key features, and backing up your information with relevant articles!<br />
<br />
===Group 1 Peer Assessment===<br />
<br />
The start you have made on your project appears to be quite decent. There seems to be a clear overview and scaffold of how your page will look and what it will discuss in the end. For the most part the usage of dot points has made understanding your points with regards to the signaling pathways (Canonical pathway section) a lot easier as opposed to having a wall of text. I would recommend possibly adopting dot points when explaining the pathway regarding the Wnt-Calcium Ion pathway to make it easier to digest. That being said though, there are areas within your wiki page that would most likely benefit from having complete paragraphs such as your sub sections labeled under the non-canonical pathway. It appears that each individual point in the sub section role appears to represent individual points that could be substantially elaborated on. In way I feel that it would make the ideas in the section less disjoint and more clear, given that writing in a paragraph format would be suitable for longer passages. Also for the part where there are there are research articles linked, and descriptions of such articles, it might be better to try integrate such ideas into other main components of your wiki page, because they seem quite out of context and out of nowhere. That being said you could also just put this under a current research heading and talk about it with respect to the current findings of the Wnt pathway. <br />
<br />
Another main aspect that should be corrected is that in some sections, there is the assumption in your wiki page that the reader fully understands all your abbreviations. I know it sounds silly but it is probably best that your group coordinates or finds where you first use an abbreviation such as CaMKII in your non canonical pathway section and change it to the unabbreviated name, with the abbreviated name in brackets, where from there you can just use the abbreviated name. Also maybe just providing a glossary of the abbreviated terms and their unabbreviated terms at the end of your page will do as well. Also its good to keep in mind that you may have already done this for some terms, so look out for that as well.<br />
<br />
With regards to your referencing, I see that it is quite extensive, but there seems to be a lack of in text citations. As a result, its quite hard for those who read your page to quickly find the appropriate citation with regards to the sentences or dot point being read. For the sections such as “Canonical Pathway: How it works” this isn’t too bad, as there is only one reference, but for the “Non-Canonical Pathway section” there are way too many for it to be easy to tell where the citations are associated to. So overall for this I recommend your group to use in-text citations. Also I’ve noticed that you have used a review to cite your whole “Canonical pathway: How it works” section, which for the most part most likely contains all your information you have stated, but doesn’t give credit to the specific or individual authors included in the review and also requires the reader to go and find the specific sections in the review that you have used to cite your text. It is such that it would be better to use research articles to site your individual points, maybe extracting such research articles from the review article itself. <br />
<br />
Overall the start made on your project is appearing to take shape, where I see that there are many subheadings yet to be filled below the “Wnt-Calcium Ion pathway” section. I’m sure if your groups keep up the quality of the work, your page should turn out fine with the addition of incorporating the feedback I have provided. <br />
<br />
<br />
===Group 1 – Wnt Signalling Pathway===<br />
Positive aspects of the project include that fact that this group has included detailed information of the different WnT signaling pathways. It does seem however, that this information would perhaps be better conveyed to the audience if it were accompanied with images (either sourced from the internet or hand drawn) and/or videos/animations, as well as some information on the role of each signaling molecule/receptor subtype (perhaps in a table) just to provide a more thorough explanation of this pathway. Furthermore, this group has made a conscious decision to include a glossary, although they have not yet started this, it is going to be something the group can add to whilst finishing the project and will help the reader better understand the concepts they discuss. This group has included a large amount of references throughout their project, including a significant amount of recent primary articles, which shows the reader that their information is well researched and very current. However, the only criticism here is that they aren't appropriately formatted for the purpose of this assignment. I would suggest that in text citations would be more appropriate, so the reader can clearly identify where this specific information is from and then go directly to said source if need be. <br />
<br />
Alternatively negative aspects of the project, which may need some revising before submitting the final version of this assignment, would be the formatting of the project as it appears relatively incomplete. Although there are some subheadings, which are helpful, it may be useful to add additional ones to these to make it a little clear for the reader. For example perhaps use a similar scaffold to the other group projects, which have included ones such as introduction, history, outline of the signaling pathway, its specific roles in embryonic development and then abnormalities specifically relating to embryonic development, as this would help break up the information better and make the projects more consistent for readers. Most of the work on this project seems to focus on explaining the signaling pathway so I assume its more the case of the group hasn’t got around to it yet, but I think more information on the role this signaling pathway specifically has in embryonic development is required, like the paragraph on early stages of skin formation, in order to tie in the assignment with what we have been learning in the labs and lectures. As mentioned I think the subheadings may need some revision, and the current ‘What can go wrong’ may be better described as ‘abnormalities’ that way you could also include a discussion of abnormalities to Wnt that specifically influence normal embryonic development, as well as still include the paragraphs on its influence on tumor cells which could perhaps be found using the ‘omim’ site searching by a receptor subtype or pathway. Also, although you have included more of a discussion of abnormalities that occur later in development, it is interesting for the reader and does go beyond our understanding from class, but the main focus probably should be on abnormalities in embryonic development. <br />
<br />
In conclusion this project is definitely on its way to being really good, the information on the signaling pathways appears to be well research. The major criticisms were mostly focused on presentational aspects of the project like subheadings, references and the inclusion of images/tables. With some more research on its role in early embryonic development and abnormalities this will be very successful. <br />
<br />
<br />
===Group 1 Peer Assessment===<br />
<br />
Positive aspects of the project and improvements:<br />
Upon initially glancing over the project you can clearly see a range on headings and subheadings and it is evident by these that the project is about the WnT signalling pathway in skin of fetus. This is sufficient for assessment criteria 1 and 2 as you can see the aspect of research they are targeting such as skin formation during embryonic development. Throughout the text you can see citations relating to the topic and a range of references at the end of the project. This satisfies the requirements for criteria 3 but just a small critique would be to put these references in the references section just to clear out the unnecessary area. It can also be commended that the group project goes above and beyond the curriculum of informing us about the background information of WnT signalling pathway in skin of fetus but also includes the complications and diseases arising due to abnormalities in the WnT pathway. This is excellent and satisfies the requirements for criteria 5<br />
There can be some improvements in the project but they are not necessarily of the utmost importance. Firstly, the group can add other specific subheadings and the relevant information under them such as the history or background of the signalling pathway. This is just so the reader has a more rounded knowledge of the pathway and can increase the interest and keep them engaged. It would also be good to see in the text and not just at the end of a paragraph. Such as, in the canonical and non canonical pathway heading it would be recommended to have in text citation and not just at the end just to show the reader where the information was gathered from.<br />
Negative aspects of the project and improvements:<br />
<br />
Although the project has a fair amount of positives there are some areas that are lacking. Firstly, the report requires additional information in each section and how this information can be linked to pathways in embryological development. It would also be recommended to put in diagrams, images, tables etc. This would engage the reader and make the read more interesting since at the moment there are no images or tables. Also doing so will satisfy one aspect of criteria 2. This way the audience can develop a visual understanding of the topic. It would be advisable to put tables in the history section in the form of relevant dates/years and the information corresponding to the year. <br />
<br />
Also, it would be good to see the role of WnT signalling pathway in something other than skin, for eg: an organ or tissue or cell. This would aid in achieving a higher mark for criteria 5 as you go above the required information. Overall it was great to see all group members contributing to the project but minor edits such as citations, images, tables, and adding additional information to sections would really captivate the reader and make it an enjoyable read. <br />
<br />
<br />
<br />
<br />
<br />
==Notes==<br />
Just trying to simplify and understand the process and these are some of my notes !(z3417363)<br />
<br />
The inactive Wnt Pathway In a normal cell:<br />
<br />
In most normal cells the Wnt pathway is inactive. In the cytosol , the destruction complex is formed from the proteins beta catenin, GSK3 beta, Axin,APC, Ck1-alpha. The ubiquitin ligase beta TRCP is able to bind to beta catenin and transfer short ubiquitin peptides to beta-catenin. In other words the beta-catenin is phosphorolated and this beta catenin can then bound and be by a complex of protease (proteasome) . Thus a low level of cellular beta catenin is achieved. <br />
Therefore no beta catenin reaches the nucleus and the transcription factor of the TCF LEF family along with other proteins (groucho) binds to DNA and inhibits gene expression.<br />
So essentially when WnT is inactive, beta canenin is destroyed and does not reach nucleus and transcription is inhibited. <br />
<br />
The Active Wnt Pathway in a normal cell.<br />
<br />
Extracellular(outside cell) Wnt binds with the membrane receptor frizzled (FZD). The wnt pathway is activated and activates the cytosolic protein "dishevelled"(DSH) which induces dissociation of the protein destruction complex. Because the protein complex is destroyed beta- catenin is no longer modified by unbiquitin peptides/phosporolated and is not destroyed. Since the supply of beta catenin continues the level of beta catenin rises, first in the cytosol and later in the nucleus. Once the beta catenin reaches the nuclue it binds to the TCF LEF transcription factor which changes them from a transcriptional repressor into an activator. TCF itself activates an RNA polymerase which induces gene transcription.<br />
So essentially WnT starts gene transcription by allowing beta catenin to reach the nucleus.<br />
<br />
This is actually very similar to a tumour cell where the mutation of the protein complex also inhibits the destruction of beta catenin and allows it to grow in quantity and reach the nucleus and start gene expression. However this is not uncontrolled and can be compared to a car travelling with no brakes. Ultimately this abnormal proliferation leads to malignant adenocarcinoma (cancer).<br />
<br />
Use pubmed, biomedcentral journals==you can find it on pubmed just plug in the title and you will get the pubmed number>BMC developmental biology journal, journal of cell biology(cant use last 6months of research), proceeding national academy of science(can only use after 6months), public library of science omim<br />
include research labs, animations<br />
use the help tab<br />
where the terminlogy came from <br />
this is a student drawn image , based upon and give the reference</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2016_Group_Project_1&diff=249618
Talk:2016 Group Project 1
2016-10-06T16:30:44Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016discussionheader}}<br />
=Peer Review=<br />
<font size="4"><u>Group 1:</u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br><br />
Upon assessment of this project, it appears that the authors have devised a variety of subheadings related to the signalling pathway of the Wnt receptor in embryonic development which is excellent. The group has also began investigating the involvement of Wnt in numerous aspects of embryonic development such as skin formation. The use of subheadings and headings related to the Wnt receptor partially meets criteria 1 and 2 assessment. It also appears that the group has cited and referenced sources for some of the information utilised, particularly when describing the “Caronical Pathway”. This also partially meets criteria 3 for this assessment. The group has also attempted to explore abnormalities in the Wnt pathway by describing interruptions in the pathway and its relation to cancer which is very interesting. They have therefore attempted to research ideas related to this receptor that extend beyond formal teaching activities, by explaining the link between Wnt abnormalities and disease (criteria 5). <br />
<br><br />
<br><br />
Whilst there are the positive aspects of the page, improvements can still be made to ensure that the group satisfies the first five points of the marking criteria. Firstly, although there appears to be subheadings, there only appear to be few and therefore it would be excellent to add more subheadings. Subheadings may relate to the history of the Wnt signalling pathway or even subtypes of the receptor as well as their respective functions. In addition, whilst the group appear to have cited some of their sources, it is important to cite all sources, particularly when gathering data under the “Non-canonical pathway” subheading. Although a series of articles have been referred to, it is vital that the group includes in-text citations in order for the audience to determine the source for each segment of information. A suggestion would be to investigate more examples of diseases caused by abnormalities in the Wnt signalling pathway<br />
<br><br />
<br><br />
<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
The group appeared to provide a general description of the abnormalities associated with disruption of the Wnt pathway; however they did not talk about abnormalities in the context of embryonic development. A suggestion would be to discuss Wnt abnormalities to the effect it has on embryonic development. It was also noticed that the group failed to include diagrams, tables or figures to reinforce the information. The use of diagrams would assist the audience in developing a visual understanding of the information presented and also makes the wiki page more appealing too. Therefore, a suggestion would be to use diagrams and figures. For example, a diagram of the signalling pathway would be a suggestion. It was noticed that the page appears to have no introduction or history describing the Wnt receptor. Therefore, a possible improvement would be to include a brief introduction and history at the beginning of the page as well as a few diagrams to provide the audience with an insight into what the receptor’s purpose is before exploring its function in embryonic developing.<br />
<br><br />
<br><br />
In addition, it appears that the group has focused on the role of Wnt in skin development of the embryo only. A possible improvement would be to investigate the involvement of Wnt in other areas of embryonic development, perhaps the development of specific organ systems or other structures.<br />
<br><br />
<br><br />
<br><br />
<br><br />
<br><br />
<br><br />
To all group members:<br />
*More info on pathway focusing on fetus development, and which pathway it is majorly part of - focus research on those body parts<br />
*Make your section presentable<br />
*At least one picture per section<br />
<br />
===Group 1===<br />
<br />
You guys have made significant progress on your project, managing to touch briefly on each section of your assignment. There have been some good choices of subheadings but I think some improvement can be made. For example, I think it would be useful to breakdown the general heading of ‘introduction’ into smaller subheadings so readers are made aware of what will be discussed in this section. It would also be useful to touch upon the importance of this pathway and thus, highlighting its significance in embryological development. <br />
<br />
In terms of the content of the project, being only in the draft stage a considerable amount of editing is required. For example, there has been mention of the TCF/LEF family and though the use of this abbreviations is useful, I think it would be appropriate to initially include the full name and explain this term in brief detail. In addition, there has been discussion of the ‘canonical’ and ‘non-canonical’ pathways of WnT Signalling Pathway but you could consider discussing the significance of having these two separate pathways. Comparing and contrasting these two pathways may also assist in aiding one’s understanding of the topic. <br />
<br />
Though it is great that you have made progress, I think more detail is required in each section, particularly in linking the effect of these pathways on embryological development. Also, greater attention needs to paid to referencing and utilisation of studies that have dissected this signalling pathway. For example, greater emphasis can be placed on studies performed on ‘embryos of Xenopus laevis’ or the in vitro experiments on mice. Instead of saying ‘a study’ or ‘another study’ acknowledge the researchers of this study as it will increase the validity of your argument while providing readers with the opportunity to refer back to these papers for more information if required or interested. More detail is also required on the effect of this pathway on skin formation. One way this could be done is by expanding on the information already provided, for example, explain how ‘WnT signalling inhibits the ectoderm’s responsiveness to FGFs’ and provide a detailed explanation of the feedback mechanism. Though your topic is focusing on ‘WnT Signalling pathway in the skin of fetus’ It would be beneficial to explore the roles of Wnt signalling in other areas of embryological development as this could provide insight into the abnormalities caused by mutations in this pathway. In terms of the ‘what can go wrong’ section, try breaking this segment into the various embryological deficiencies that can develop through disruption of the WnT pathway and try and make it relevant by providing statistics. <br />
<br />
Overall, you guys have done a fantastic job! It was good to see that all group members had contributed to the project. The main thing that requires improvement is the lack of detail. Through editing and inclusion of appropriate references and citations you can significantly improve the quality of your work. It would be useful to add some diagrams or images to help explain the pathway. In addition, try utilising your discussion page and communicating with your other team members. By providing feedback and suggestions you can assist in efficiently producing an excellent project. I hope this helps!! <br />
<br />
===Group 1 Critical Assessment===<br />
In terms of the topic of WnT signalling pathway, the page is beginning to come together with a great amount of information. What I particularly like is how the different concepts introduced in the page have been explained, for e.g. the different WnT pathways. However the content for each pathway does not seem to be consistent. While the canonical pathway addresses the mechanism, the non-canonical one doesn’t. I would suggest constructing a table to compare the similarities and differences between the various pathways, and adding images or shorts clips with audio to represent the elements of the pathways in a different form. This would not only enhance the look of your page but also make it more interactive for the audience. <br />
<br />
A great positive is to see links to research articles have been provided for the audience to access if they are interested to read on further. The links are short and easy to see, and direct you straight to the article on Pubmed, a reliable source. An effort has also been made to summarise the article, however the summary should be available as a simple breakdown so the audience can refer to it if they struggle to understand. The summaries include some jargon that can be further simplified. <br />
<br />
In relation to criteria 1, the key points have definitely been highlighted and the signalling pathway has been associated with the fetal development, however to make it more interesting and satisfy criteria 5, possibly construct a table or briefly outline how WnT signalling is involved in other areas such as Type 2 Diabetes and Cancer. Furthermore, to relate the topic back to embryological development explore the pathway in other areas such as gastrulation, rather than limiting discussion to skin development.<br />
<br />
Lastly to satisfy criteria 3, attempt to include in text citations within the paragraphs, instead of displaying references towards the end of the page. Overall, great job in gathering and highlighting key features, and backing up your information with relevant articles!<br />
<br />
===Group 1 Peer Assessment===<br />
<br />
The start you have made on your project appears to be quite decent. There seems to be a clear overview and scaffold of how your page will look and what it will discuss in the end. For the most part the usage of dot points has made understanding your points with regards to the signaling pathways (Canonical pathway section) a lot easier as opposed to having a wall of text. I would recommend possibly adopting dot points when explaining the pathway regarding the Wnt-Calcium Ion pathway to make it easier to digest. That being said though, there are areas within your wiki page that would most likely benefit from having complete paragraphs such as your sub sections labeled under the non-canonical pathway. It appears that each individual point in the sub section role appears to represent individual points that could be substantially elaborated on. In way I feel that it would make the ideas in the section less disjoint and more clear, given that writing in a paragraph format would be suitable for longer passages. Also for the part where there are there are research articles linked, and descriptions of such articles, it might be better to try integrate such ideas into other main components of your wiki page, because they seem quite out of context and out of nowhere. That being said you could also just put this under a current research heading and talk about it with respect to the current findings of the Wnt pathway. <br />
<br />
Another main aspect that should be corrected is that in some sections, there is the assumption in your wiki page that the reader fully understands all your abbreviations. I know it sounds silly but it is probably best that your group coordinates or finds where you first use an abbreviation such as CaMKII in your non canonical pathway section and change it to the unabbreviated name, with the abbreviated name in brackets, where from there you can just use the abbreviated name. Also maybe just providing a glossary of the abbreviated terms and their unabbreviated terms at the end of your page will do as well. Also its good to keep in mind that you may have already done this for some terms, so look out for that as well.<br />
<br />
With regards to your referencing, I see that it is quite extensive, but there seems to be a lack of in text citations. As a result, its quite hard for those who read your page to quickly find the appropriate citation with regards to the sentences or dot point being read. For the sections such as “Canonical Pathway: How it works” this isn’t too bad, as there is only one reference, but for the “Non-Canonical Pathway section” there are way too many for it to be easy to tell where the citations are associated to. So overall for this I recommend your group to use in-text citations. Also I’ve noticed that you have used a review to cite your whole “Canonical pathway: How it works” section, which for the most part most likely contains all your information you have stated, but doesn’t give credit to the specific or individual authors included in the review and also requires the reader to go and find the specific sections in the review that you have used to cite your text. It is such that it would be better to use research articles to site your individual points, maybe extracting such research articles from the review article itself. <br />
<br />
Overall the start made on your project is appearing to take shape, where I see that there are many subheadings yet to be filled below the “Wnt-Calcium Ion pathway” section. I’m sure if your groups keep up the quality of the work, your page should turn out fine with the addition of incorporating the feedback I have provided. <br />
<br />
<br />
===Group 1 – Wnt Signalling Pathway===<br />
Positive aspects of the project include that fact that this group has included detailed information of the different WnT signaling pathways. It does seem however, that this information would perhaps be better conveyed to the audience if it were accompanied with images (either sourced from the internet or hand drawn) and/or videos/animations, as well as some information on the role of each signaling molecule/receptor subtype (perhaps in a table) just to provide a more thorough explanation of this pathway. Furthermore, this group has made a conscious decision to include a glossary, although they have not yet started this, it is going to be something the group can add to whilst finishing the project and will help the reader better understand the concepts they discuss. This group has included a large amount of references throughout their project, including a significant amount of recent primary articles, which shows the reader that their information is well researched and very current. However, the only criticism here is that they aren't appropriately formatted for the purpose of this assignment. I would suggest that in text citations would be more appropriate, so the reader can clearly identify where this specific information is from and then go directly to said source if need be. <br />
<br />
Alternatively negative aspects of the project, which may need some revising before submitting the final version of this assignment, would be the formatting of the project as it appears relatively incomplete. Although there are some subheadings, which are helpful, it may be useful to add additional ones to these to make it a little clear for the reader. For example perhaps use a similar scaffold to the other group projects, which have included ones such as introduction, history, outline of the signaling pathway, its specific roles in embryonic development and then abnormalities specifically relating to embryonic development, as this would help break up the information better and make the projects more consistent for readers. Most of the work on this project seems to focus on explaining the signaling pathway so I assume its more the case of the group hasn’t got around to it yet, but I think more information on the role this signaling pathway specifically has in embryonic development is required, like the paragraph on early stages of skin formation, in order to tie in the assignment with what we have been learning in the labs and lectures. As mentioned I think the subheadings may need some revision, and the current ‘What can go wrong’ may be better described as ‘abnormalities’ that way you could also include a discussion of abnormalities to Wnt that specifically influence normal embryonic development, as well as still include the paragraphs on its influence on tumor cells which could perhaps be found using the ‘omim’ site searching by a receptor subtype or pathway. Also, although you have included more of a discussion of abnormalities that occur later in development, it is interesting for the reader and does go beyond our understanding from class, but the main focus probably should be on abnormalities in embryonic development. <br />
<br />
In conclusion this project is definitely on its way to being really good, the information on the signaling pathways appears to be well research. The major criticisms were mostly focused on presentational aspects of the project like subheadings, references and the inclusion of images/tables. With some more research on its role in early embryonic development and abnormalities this will be very successful. <br />
<br />
<br />
===Group 1 Peer Assessment===<br />
<br />
Positive aspects of the project and improvements:<br />
Upon initially glancing over the project you can clearly see a range on headings and subheadings and it is evident by these that the project is about the WnT signalling pathway in skin of fetus. This is sufficient for assessment criteria 1 and 2 as you can see the aspect of research they are targeting such as skin formation during embryonic development. Throughout the text you can see citations relating to the topic and a range of references at the end of the project. This satisfies the requirements for criteria 3 but just a small critique would be to put these references in the references section just to clear out the unnecessary area. It can also be commended that the group project goes above and beyond the curriculum of informing us about the background information of WnT signalling pathway in skin of fetus but also includes the complications and diseases arising due to abnormalities in the WnT pathway. This is excellent and satisfies the requirements for criteria 5<br />
There can be some improvements in the project but they are not necessarily of the utmost importance. Firstly, the group can add other specific subheadings and the relevant information under them such as the history or background of the signalling pathway. This is just so the reader has a more rounded knowledge of the pathway and can increase the interest and keep them engaged. It would also be good to see in the text and not just at the end of a paragraph. Such as, in the canonical and non canonical pathway heading it would be recommended to have in text citation and not just at the end just to show the reader where the information was gathered from.<br />
Negative aspects of the project and improvements:<br />
Although the project has a fair amount of positives there are some areas that are lacking. Firstly, the report requires additional information in each section and how this information can be linked to pathways in embryological development. It would also be recommended to put in diagrams, images, tables etc. This would engage the reader and make the read more interesting since at the moment there are no images or tables. Also doing so will satisfy one aspect of criteria 2. This way the audience can develop a visual understanding of the topic. It would be advisable to put tables in the history section in the form of relevant dates/years and the information corresponding to the year. <br />
Also, it would be good to see the role of WnT signalling pathway in something other than skin, for eg: an organ or tissue or cell. This would aid in achieving a higher mark for criteria 5 as you go above the required information. Overall it was great to see all group members contributing to the project but minor edits such as citations, images, tables, and adding additional information to sections would really captivate the reader and make it an enjoyable read. <br />
<br />
<br />
<br />
<br />
<br />
==Notes==<br />
Just trying to simplify and understand the process and these are some of my notes !(z3417363)<br />
<br />
The inactive Wnt Pathway In a normal cell:<br />
<br />
In most normal cells the Wnt pathway is inactive. In the cytosol , the destruction complex is formed from the proteins beta catenin, GSK3 beta, Axin,APC, Ck1-alpha. The ubiquitin ligase beta TRCP is able to bind to beta catenin and transfer short ubiquitin peptides to beta-catenin. In other words the beta-catenin is phosphorolated and this beta catenin can then bound and be by a complex of protease (proteasome) . Thus a low level of cellular beta catenin is achieved. <br />
Therefore no beta catenin reaches the nucleus and the transcription factor of the TCF LEF family along with other proteins (groucho) binds to DNA and inhibits gene expression.<br />
So essentially when WnT is inactive, beta canenin is destroyed and does not reach nucleus and transcription is inhibited. <br />
<br />
The Active Wnt Pathway in a normal cell.<br />
<br />
Extracellular(outside cell) Wnt binds with the membrane receptor frizzled (FZD). The wnt pathway is activated and activates the cytosolic protein "dishevelled"(DSH) which induces dissociation of the protein destruction complex. Because the protein complex is destroyed beta- catenin is no longer modified by unbiquitin peptides/phosporolated and is not destroyed. Since the supply of beta catenin continues the level of beta catenin rises, first in the cytosol and later in the nucleus. Once the beta catenin reaches the nuclue it binds to the TCF LEF transcription factor which changes them from a transcriptional repressor into an activator. TCF itself activates an RNA polymerase which induces gene transcription.<br />
So essentially WnT starts gene transcription by allowing beta catenin to reach the nucleus.<br />
<br />
This is actually very similar to a tumour cell where the mutation of the protein complex also inhibits the destruction of beta catenin and allows it to grow in quantity and reach the nucleus and start gene expression. However this is not uncontrolled and can be compared to a car travelling with no brakes. Ultimately this abnormal proliferation leads to malignant adenocarcinoma (cancer).<br />
<br />
Use pubmed, biomedcentral journals==you can find it on pubmed just plug in the title and you will get the pubmed number>BMC developmental biology journal, journal of cell biology(cant use last 6months of research), proceeding national academy of science(can only use after 6months), public library of science omim<br />
include research labs, animations<br />
use the help tab<br />
where the terminlogy came from <br />
this is a student drawn image , based upon and give the reference</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z5014803&diff=249552
User:Z5014803
2016-10-06T10:58:12Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Student2016}}<br />
<br />
==Lab Attendance==<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 18:29, 5 August 2016 (AEST)<br />
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[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:40, 12 August 2016 (AEST)<br />
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[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:07, 19 August 2016 (AEST)<br />
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[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:09, 26 August 2016 (AEST)<br />
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[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:45, 2 September 2016 (AEST)<br />
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[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:13, 9 September 2016 (AEST)<br />
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[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:46, 23 September 2016 (AEST)<br />
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<br />
===Belbin Team Roles===<br />
In my previous courses, I was introduced to the Bebin model team roles as a way to identify myself in a team scenario. I definitely see myself as a "Shaper" since I am driven to try and complete the task at hand as soon as possible to ensure sufficient time for the editing process and the refining of the task. I also agree that I motivate other team members to progress through the task at a efficient pace such that the group does not lose momentum. I am also a person who is not afraid to speak my mind and thus will contest other viewpoints in order to spark a discussion. I identify myself as a very dynamic person in the way that I act according to the different predicaments I'm in and this results in numerous ways of efficiently solving any problems. Although I identify myself as a Shape I do not agree that i can become aggressive or bad humoured as I see some traits of a Co-ordinator in me. I have a very mature approach and recognise that each individual has a different way of attacking a problem and have learnt to appreciate others. <br />
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===Lecture 1: Fertilisation===<br />
I have always been fond of the details surrounding fertilisation as it seems like a very interesting topic. It is more than just a sperm and egg cell coming together. The first lecture on fertilisation highlighted the various processes that need to occur in order to form a zygote, from gametogenesis to fertilisation and then forming the zygote. In my first year studies I learnt that there is a mechanism to prevent multiple sperm cells to enter the ovum but wasnt familiar with the process. The most interesting aspect of this lecture was precisely the process from fertilisation to the prevention of polyspermy. I was intrigued by how sperm cells are attracted to the oocyte which was through the ZP2 protein and only the nucleus of the spermatozoa enters the cell membranes. I was also interested in how membrane fusion will result in oocyte processes that will prevent polyspermy through the elevation of intracellular calcium levels. I had minimal knowledge of this topic but the lecture really made me want to learn about this process in a lot more detail. <br />
<br />
==New SubHeading==<br />
===External Link===<br />
[http://www.smh.com.au/ SMH]<br />
<br />
===Internal Link===<br />
[[ANAT2341 Lab 1]]<br />
<br />
[[ANAT2341 Lab 1|Fertilization Lab]]<br />
<br />
[[Student Page]]<br />
<br />
==Referencing==<br />
[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=fertilization fertilization]<br />
<br />
PMID 27486480<br />
<br />
==Assessment 1==<br />
<br />
<pubmed>27486266</pubmed> <br />
<br />
In order for fertilization to occur spermatozoa must be activated in a process known as 'sperm capacitation'. The primary research article "Seminal vesicle proteins SVS3 and SVS4 facilitate SVS2 effect on sperm capacitation" by Araki et al (2016) investigate the role of seminal vesicle secretion and how they inhibit the activation of spermatozoa and how they reduce the fertility of the capacitated spermatozoa (decapacitation). In previous studies it has already been shown that SVS2 acts as a capacitation inhibitor and a decapacitation factor and Araki et al (2016) build up on this pre existent knowledge about SVSs other than SVS2. The investigation utilised CD-1 mice, in particular female mice, to show the effects of SVS3 and SVS4 on sperm cells in the female reproductive tract. <br />
<br />
<br />
Levels of SVS3 and SVS4 were measured in each part of the female reproductive tract such as the copulaatory plug, vagina, oviduct and uterine region near the vagina and oviduct 1.5 hours post copulation. By using anti SVS3 antibody there were clear indications as to the specific roles of SVS3. Results showed that there were no SVS3 proteins in any of the aforementioned parts of the reproductive tract and thus the protein alone had no effects on sperm capacitation. In saying that, SVS3 proteins did show that they had the ability to potentiate the effects of SVS2. Similarly anti SVS4 antibody was utilised to provide insight into the function of this particular protein. Contrary to the findings for SVS3, SVS4 was detected in the uterus but not in any other part of the tract. This suggests that SVS4 has similar activity to that of SVS2 in a way that both the proteins enter the uterus. Thus, SVS4 acts as a capacitation inhibitor similar to SVS2 but results indicated that it does not have the decapacitation effect like SVS2.<br />
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{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 18 August 2016 - You have added the citation correctly and written a good summary of this very recent article, still only available in the pre-published submitted format, findings. One thing, you must always include the full term in your summary (even if it appears in the paper title) before you begin to use the acronym. "SVS" (seminal vesicle protein secretion) could and may mean different things in different contexts.<br />
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| width=100px| Assessment 5/5<br />
|}<br />
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==Assessment 2==<br />
<br />
[[File:Development_of_mouse_embryo_in_early_stages.png|400px|thumb|centre|Live imaging of the whole mouse embryo at E6 (A to D) and E5.5. (E to H)<ref><pubmed>23861733</pubmed></ref>]]<br />
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{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 29 August 2016 - Reference and Copyright correctly included with the file and referenced on your page here. You have not included the <nowiki>{{Student Image}}</nowiki> template in the file summary box.<br />
<br />
| Assessment 4.5/5<br />
|}<br />
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===References===<br />
<br />
<br />
<br />
== Lab 3 Assessment ==<br />
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{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 31 August 2016 - Lab 3 Assessment Quiz - [[Lecture_-_Mesoderm_Development|Mesoderm]] and [[Lecture_-_Ectoderm_Development|Ectoderm]] development. All correct, Well done!<br />
<br />
| Assessment 5/5<br />
|}<br />
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<br />
==Assessment 4==<br />
==Quiz==<br />
<br />
<quiz display=simple><br />
<br />
{Which of the following structures does the ectoderm contribute to?<br />
|type="()"}<br />
- epithelium, mesentry, connective tissue<br />
+ enteric nervous system<br />
- epithelium and smooth muscle<br />
- enteric nervous system, connective tissue, smooth muscle<br />
|| Option two is correct as the ectoderm only contributes to the enteric nervous system. Epithelium is contributed by the endoderm, whereas the mesentry, connective tissues, smooth muscle, blood vessels are contributed by the mesoderm<br />
<br />
{What lies rostral in relation to the notochord?<br />
|type="()"}<br />
- mesoderm<br />
- the neural tube<br />
+ the buccopharyngeal membrane<br />
- the mesoderm then endoderm<br />
|| The buccopharyngeal membrane lies rostral in relation to the notochord. The mesoderm lies laterally to the notochord, the neural tube dorsally and the mesoderm and endoderm ventrally.<br />
<br />
{During Week 8- 10 (GA 10- 12 weeks):<br />
|type="()"}<br />
+ neural crest migrates into the wall forms enteric nervous system<br />
- endoderm in the GIT wall proliferates<br />
- a second rotation (of 90 degrees) occurs on the longitudinal axis establishing the adult orientation of the stomach.<br />
- mesoderm within the dorsal mesogastrium form a long strip of cells adjacent to the forming stomach above the developing pancreas<br />
|| Option A is correct and is the only one that occurs during weeks 8-10. Option B occurs at the beginning of Week 5. Option C occurs during Week 4. Option D also occurs in Week 5 and is incorrect<br />
<br />
{Narrowing of a lumen such as the duodenum or the pylorus is also called:<br />
|type="()"}<br />
- duplication<br />
- atresia.<br />
+ stenosis<br />
- gastroschisis<br />
|| Stenosis is the correct answer. Duplication is the incomplete recanalization resulting in parallel lumens, this is really a specialized form of stenosis. Atresia is the interuption of the lumen and gastroschisis is a congenital abdominal wall defect which results in herniation of fetal abdominal viscera into the amniotic cavity.<br />
<br />
</quiz><br />
<br />
[[Student Page]]<br />
<br />
==Lab 6 Assessment==<br />
<br />
Completed ANAT2341 Lab 5 - Course Feedback Questionnaire<br />
<br />
==Lab 6 Assessment==<br />
<br />
===Identify a known genetic mutation that is associated with cleft lip or palate===<br />
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Tbx22 mutations are associated with cleft lip/palate<br />
<br />
===Identify a recent research article on this gene===<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/21375406 Arunee Kaewkhampa, D.D.S., M.S., Dhirawat Jotikasthira, D.D.S., M.S., Sutti Malaivijitnond, D.D.S., M.S.,<br />
Piranit Kantaputra, D.D.S., M.S '''TBX22 Mutation Associated With Cleft Lip/Palate, Hypodontia, and Limb Anomaly''' Cleft Palate Craniofacial Journal.: 2012, 49(2); 240-4 PubMed 21375406]<br />
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===How does this mutation affect developmental signalling in normal development===<br />
<br />
<br />
==Lab 7 Assessment==<br />
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===Muscular Dystrophy===<br />
<br />
'''''What is/are the dystrophin mutation(s)?'''''<br />
<br />
The mutations in the dystrophin gene can sequentially lead to two types of muscular dystrophies; Duchene (DMD) and Becker (BMD) muscular dystrophy. DMD is the largest known gene in humans measuring 2.4Mb. The gene provides the coding for the a protein called dystrophin which is located primarily in muscles (skeletal and cardiac) and in minor quantities in nerve cells. In most cases mutations in this gene are of the deletion type in which pieces of DNA are lost. Other types of mutations include large duplications (pieces of DNA are copied) and point mutations (small changes in the DNA code). The aforementioned dystrophies arise from deletions in the dystrophin gene. <br />
<ref name="PMID23961084 "><pubmed>23961084</pubmed></ref><br />
<br />
<br />
'''''What is the function of dystrophin?'''''<br />
<br />
The dystrophin protein provides a structural link between the cytoskeleton of muscles and the extracellular matrix which attributes to maintaining the muscle integrity. It is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Although not much is known about the protein it is thought to cause membrane stabilisation and a lack of the protein can activate multiple pathophysiological processes. <br />
<ref name="PMID11917091"><pubmed>11917091</pubmed></ref><br />
<br />
<br />
'''''What other tissues/organs are affected by this disorder?'''''<br />
<br />
A gradual deterioration in lung function occurs as respiratory muscles weaken resulting in respiratory failure. The heart can also be affected in 1 of 2 ways namely abnormal heart rhythms and cardiomyopathy. <br />
<br />
<br />
<br />
'''''What therapies exist for DMD?'''''<br />
<br />
There is no cure for the disease as of yet but there are various research programs worldwide tackling this issue. There are also measures that can help manage the condition and improve quality of life. These include exercise, supportive environment, medical treatment (steroid treatment mostly), nutrition, surgeries, and palliative care. Other therapies that are currently under going research include gene therapy, reading through stop signals, stem cell therapy, utrophin upregulation, moosting muscle growth and reducing muscle damage<br />
<ref name="PMID22533379"><pubmed>22533379</pubmed></ref> <br />
<br />
<br />
'''''What animal models are available for muscular dystrophy?'''''<br />
<br />
The mouse is used animal model for muscular dystrophy. Other animal that have been utilised include the golden retriever dog and pigs. <br />
<ref name="PMID22137430"><pubmed>22137430</pubmed></ref><br />
<br />
=<u>Lab 9 Peer Review</u>=<br />
<br><br />
<font size="4"><u>Group 1:</u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br><br />
Upon initially glancing over the project you can clearly see a range on headings and subheadings and it is evident by these that the project is about the WnT signalling pathway in skin of fetus. This is sufficient for assessment criteria 1 and 2 as you can see the aspect of research they are targeting such as skin formation during embryonic development. Throughout the text you can see citations relating to the topic and a range of references at the end of the project. This satisfies the requirements for criteria 3 but just a small critique would be to put these references in the references section just to clear out the unnecessary area. It can also be commended that the group project goes above and beyond the curriculum of informing us about the background information of WnT signalling pathway in skin of fetus but also includes the complications and diseases arising due to abnormalities in the WnT pathway. This is excellent and satisfies the requirements for criteria 5<br />
<br><br />
<br><br />
There can be some improvements in the project but they are not necessarily of the utmost importance. Firstly, the group can add other specific subheadings and the relevant information under them such as the history or background of the signalling pathway. This is just so the reader has a more rounded knowledge of the pathway and can increase the interest and keep them engaged. It would also be good to see in the text and not just at the end of a paragraph. Such as, in the canonical and non canonical pathway heading it would be recommended to have in text citation and not just at the end just to show the reader where the information was gathered from.<br />
<br><br />
<br><br />
<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Although the project has a fair amount of positives there are some areas that are lacking. Firstly, the report requires additional information in each section and how this information can be linked to pathways in embryological development. It would also be recommended to put in diagrams, images, tables etc. This would engage the reader and make the read more interesting since at the moment there are no images or tables. Also doing so will satisfy one aspect of criteria 2. This way the audience can develop a visual understanding of the topic. It would be advisable to put tables in the history section in the form of relevant dates/years and the information corresponding to the year. <br />
<br><br />
<br><br />
Also, it would be good to see the role of WnT signalling pathway in something other than skin, for eg: an organ or tissue or cell. This would aid in achieving a higher mark for criteria 5 as you go above the required information. Overall it was great to see all group members contributing to the project but minor edits such as citations, images, tables, and adding additional information to sections would really captivate the reader and make it an enjoyable read. <br />
<br><br />
<br><br />
<font size="4"><u>Group 3:</u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements: </b><br />
<br><br />
<br><br />
The group project looks terrific at the initial glance. You can clearly see all the headings and subheadings. In particular, it is great to see a range of subheadings such as “limb bud formation”, “bone development”, “kidney development”. This shows that there was a lot of research put into this project. Also by doing so you have made it clear that your project is about the Fibroblast Growth Factor Receptor Pathway (FGFR). The page is also very easy to navigate as well which was nice to see. <br />
<br><br />
<br><br />
It is also great to see that there is addition of tables, images, and diagrams as it kept the read a lot more interesting and captivating. This allowed you to successfully satisfy criteria 2. It is also good to see correct in text citations and references as this allowed the reader to search for additional information if interested or necessary. Although you haven’t made up any multiple choice questions it is excellent to see a MCQ section. This is a great way to test the readers’ knowledge and in turn you can reflect if you have provided accurate and sufficient information to answer these questions. <br />
<br><br />
<br><br />
It was great to see that you added an abnormalities section and in particular different types of syndromes and disorders. This meant that you went over the minimum information required and put in extra effort to create a coherent project. This satisfied criteria 5 and thus a better project. Overall there are many positives in this report and with minor amendments such as adding information to sections such as “Apert syndrome”, “Animal models”, “Kidney development”, “external genitalia development” etc, a very articulate and well rounded project will be created.<br />
<br><br />
<br><br />
<br />
<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Although there are many positives in the project, there should be some amendments to the project just to ensure all bases are covered. Firstly, it would be advised to increase the amount of information to the introduction and history sections. As these sections are lacking information, the reader may not have enough information to carry on reading as their base on this topic isn’t really strong and lacks information. This can easily turn off new readers and inhibit further exploration of the topic/ project. By adding additional dates in the history section, a better overall knowledge and background of the signalling pathway can be developed which can only enhance learning. <br />
<br><br />
<br><br />
Overall, there are not many negatives and I believe as a reader your project was a great example of progress so far and with the aforementioned minor tweaks, your group is well on their way to achieving extremely high marks. <br />
<br><br />
<br><br />
<font size="4"><u>Group 4:</u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
At initial glance I can see a range of headings and subheadings which just made it easier to navigate from one aspect of the project to another. This satisfied the requirements for criteria 1 and 2. This also allowed me to recognise the main topic of the project is the Hedgehog signalling pathway. There is also an addition of an image of the pathway which was great to see as it outlines the main components of the pathway and in general educates the reader about the signalling pathway. This provided a visual stimulus/ description which in turn engaged the reader to find out more about the topic.<br />
<br><br />
<br><br />
It was also good to see correct in text citations and a references list at the end which in turn satisfied criteria 3. To satisfy criteria 5 it was excellent to see information that was well beyond the required information. An example of this is when discussing the role of the pathway in not only humans but also in mice, chicks and fruit flies. The group also began to include new research and abnormalities related to the Shh pathway which aided in rounding off criteria 1. <br />
<br><br />
<br><br />
In order to improve the already positives of this project it would be advised to add a description to the image just so the reader can have some sort of summary about the main points of the image/ pathway. Also, addition of diagrams or tables in some of the subheadings would be good as it will keep the reader interested and in general provide a visual aid. Also it is necessary to cite and provide a reference of the image as it breaches the copyright laws. <br />
<br><br />
<br><br />
<b>Negative aspects of the project and suggested improvements: </b><br />
<br><br />
<br><br />
Although there are positives to the project, there are a few negatives that can easily be fixed. It is crucial to put in an “Introduction” heading and providing relevant information. This in turn will create a coherent project as it flows from one aspect to another whilst simultaneously providing a brief overview of the Sonic Hedgehog Pathway. Although you have explored the mechanism in animal models it is imperative to link this to embryological development. Also, addition of diagrams, interactive quizzes and tables is necessary to satisfy criteria 3, since 1 image is not enough. <br />
<br><br />
<br><br />
Adding a glossary of terms at the end of the project is needed to clarify any words or phrases that have not been previously encountered such as “organogenesis”, “paracrine”, “dephosphorylation” etc. Overall, the project is coming along nicely and with the recommended amendments, a high mark is definitely in order. <br />
<br><br />
<br><br />
<font size="4"><u>Group 5: </u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Upon reviewing the page, it is evident that there has been a lot of research put in this project. Initially, there is evidence of a range of headings and subheadings which allowed the navigation from one aspect of the project to another extremely easy. This allowed me to confirm that the project is about T-box genes and their signalling. Secondly, it was excellent to see a range of images, tables and graphs as they provided visual aids to learn more about the topic and in general made it easier to accumulate information. Also it was good to see that these tables and images were correctly cited and referenced at the end which meant that there was no breach of copyright laws. <br />
<br><br />
<br><br />
Also, throughout the project there was sufficient amount of information in each subheading which meant that the reader gained all relevant information pertaining to the section that they are reading. It was also great to see a range of abnormalities being added to the project. This meant that you have went above and beyond the scope of the assessment and researched that extra bit to provide additional information about the signalling pathway and complications arising from any mutations. This meant that you successfully satisfied criteria 5 and thus a more rounded project. <br />
<br><br />
<br><br />
<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
This project certainly contains a range of positives but there were minimal negatives that can easily be amended in order to achieve a very high mark. I noticed that there was more than 1 image being used from Wikipedia and the criterion clearly says that a maximum of 1 was allowed. This is not a big deal but just in case there is harsh marking and penalties, it is advised to replace the additional image with another image. In addition, it would be useful to add a glossary of all the terms that one may find confusing such as “homologues”, “heterozygous”, “homology”, “notochord” etc. This in turn will provide the reader with enough information to understand the context of the project and in turn keep them engaged.<br />
<br><br />
<br><br />
Another negative aspect of the project was that the subheading “Ancient origins and evolution of the T-box gene family” randomly appearing nearing the end of the project. This looked a bit out of place and not flowing with the rest of the passage. To correct this it would be advised to add this to the start of the page with the “Origin of the T-box genes” section just so the information clearly flows from one topic to another without creating confusion. Overall, this project is coming along quite nicely. It is evident that a lot of research has been put into constructing a coherent and succinct project but also have the visual cues to back up the main aspects. To maximise marks, it is recommended to reflect on the feedback and correct the minor mistakes. <br />
<br><br />
<br><br />
<font size="4"><u>Group 6:</u></font><br />
<br><br />
<br><br />
<b>Positive aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Upon reviewing the page I can see a number of headings and subheadings such as the nature of the growth factor, its mechanism of action, history and emerging research. But to be critical, a range of other headings is necessary to ensure all bases are covered when researching and providing the relevant information. This will help in satisfying the requirements for criteria 1 and 2. It is good to see the addition of a diagram to your project as it is a requirement for criteria 2. This provided a visual aid that kept me interested to find out more about the topic while simultaneously making it easier to understand the theory behind the process of TGF Beta signalling pathway. It is also great to see the current research and limitations as this shows that you are going beyond the scope of the required criteria and researching ahead to provide that extra bit of information. This in turn is a great way to satisfy criteria 5.<br />
<br><br />
<br><br />
<b>Negative aspects of the project and suggested improvements:</b><br />
<br><br />
<br><br />
Although there are a few positives in the project, there are a number of negatives which can be improved upon to ensure a coherent project is created. Firstly, it is advised to put the heading “history of TGF- beta signalling pathway at the top” with the introduction as this is an introductory section and should be addressed initially on the page. This will allow you to create a more flowing page which also looks nice. Secondly, it would be advised to add more images and tables as it is a requirement for criteria 2. By doing this you will keep the reader engaged and wanting to find out more about the chosen topic. In saying that, you already have a couple of images but not referenced. It is imperative to correctly cite and reference these images as failure to do so will result in a breach of copyright laws. <br />
<br><br />
<br><br />
Another critique is to add more subheadings with a range of different aspects of the signalling pathway being explored. It is recommended that you dedicate a chunk of your project to describing the pathway in detail and its role in embryonic development and abnormalities relating to mutations caused by the pathway. This will ensure you answer criteria 6 as it is a great deal of the report. It is also advised to put the history section under the introduction section as placing it in the middle of the project is a bit out of place and inhibits the flow of the information from one subheading to another. Also, the history section can be improved by adding more information as there have been more findings in this research topic since the 1970s. An addition of glossary is also needed for terms such as “peptide”, “cytokine”, “angiogenesis”, “protein kinase” etc. This will aid readers understand terms that they previously have not encountered and allow them to correctly understand the context of the information. <br />
<br><br />
<br><br />
It has also come to my attention that there are little to no references or in text citations. By adding information without correctly giving the authors credit is a breach of copyright laws and must be done urgently. Overall, the project shows signs of progress with a number of positives. By reflecting on the negative aspects and acting upon it, it is certain that high marks are in order.</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=2016_Group_Project_2&diff=249386
2016 Group Project 2
2016-10-04T05:40:56Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016header}}<br />
{{Group Assessment Criteria table}}<br />
<!-- Do not delete the above template from the Group project page. --><br />
<br />
==Notch signalling pathway==<br />
===Introduction===<br />
The Notch signalling pathway is the most prevalent form of intracellular communication in multicellular organism. The pathway is critical for cell differentiation, proliferation, and apoptosis. It is involved in embryonic organ development through the regulation of cell-cell signalling; specifically lateral inhibition, formation of boundaries, and cell lineage assignation.<ref name="The Developing Human">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2015). The developing human: clinically oriented embryology (10th ed.). Philadelphia: Saunders.</ref><ref name=PMID10075488><pubmed>10075488</pubmed></ref> This pathway is also actively involved in adjacent cell communication, developmental process such as adult homeostasis and stem cell maintenance. Since this pathway is an intricate and crucial aspect of an organisms development and cell signalling, a mutation in the functional components of this pathway can cause a myriad of diseases such as congenital disorders, cancers, strokes, Alagille syndrome and leukoencephalopathy. <ref name=PMID19255248><pubmed>19255248</pubmed></ref> The Notch signalling process primarily utilises a ligand- receptor interaction to release protein fragments at the cellular membrane that provide signals to the internal aspect of the cell and to the adjacent cells. In mammals the Notch signalling pathway is comprised of 4 receptors (Notch 1-4) which are bounded by the Delta and Jagged ligands that bring about the activation of this pathway. <br />
<br><br><br />
<br />
===History===<br />
{| class="pretty table"<br />
| 1914<br />
| First description of a "notch" defect (loss of tissue in the wing) in ''Drosophila'' by John S. Dexter, giving the gene its name<br />
|-<br />
| 1917<br />
| First allele of ''Notch'' is identified by Thomas Hunt Morgan<br />
|-<br />
| 1930s<br />
| Donald F. Poulson conducts research into the involvement of ''Notch'' in development<br />
|-<br />
| 1958<br />
| An investigation by W.J. Welshons confirmed that the locus of Notch is contained within the 3C7 band of the X chromosome.<br />
|-<br />
| 1983<br />
| DNA sequences belonging to the Notch locus cloned and determined that RNA is required for the function of the wild type Notch. Further insight developed into the function of Notch and its role in differentiation and regeneration.<br />
|-<br />
| 1986<br />
| The molecular analysis and sequence of the Notch locus was determined by Michael W Young and his team. A relationship was identified between the protein encoded by the major Notch transcript and mammalian clotting and growth factors <br />
|-<br />
| 1989<br />
| Neurogenic loci "Delta" and "Mastermind" identified and research conducted to search for genes which may have an interaction with the Notch protein. It was confirmed that mutations in these loci will affect neurogenesis.<br />
|}<br />
<br />
===Overview of Molecular Mechanisms===<br />
Mammals possess a total of four ''Notch'' genes, with five genes for encoding the associated ligands, Delta-like and Jagged. The ''Notch'' genes each code for a single transmembrane receptor. Extracellularly, it contains epidermal growth factor (EGF)-like repeats for ligand interaction and Lin-12-Notch (LN) repeats for regulating the interactions between the extracellular and intracellular regions. Intracellularly, Notch has seven ankyrin (ANK) repeats and a transactivation domain (TAD), as well as a proline, glutamine, serine, threonine-rich (PEST) domain for degradation of Notch.<br />
<br><br><br />
====Canonical pathway====<br />
[[File:Overview of Notch signalling.png|thumb|500px|Summary of canonical Notch signalling<ref><pubmed>27404588</pubmed></ref>]]<br />
The canonical Notch pathway is unique in that it involves direct interaction between adjacent cells, as opposed to paracrine signalling, because both the Notch ligands and Notch receptors are transmembrane proteins found in the cell membrane. Furthermore, the lack of a secondary messenger or amplification process means that the Notch pathway has limited opportunities for regulation and must therefore be tightly controlled. Depending on its developmental and cellular context, activation or inhibition of the pathway can result in a variety of cellular responses, including cell death, proliferation, or differentiation.<ref name="Introduction to Notch Signalling">Yamamoto, S., Schulze, K.L. & Bellen, H.J. (2014). Introduction to Notch Signalling. ''Notch Signaling: Methods and Protocols''. Methods in Molecular Biology: 1187</ref><br />
<br><br><br />
Four Notch proteins are involved in the canonical pathway. NOTCH1 to NOTCH4 are single transmembrane receptors and can interact with a variety of ligands, including NOTCH ligands (e.g. Delta ligands) and Serrate ligands. There are three Delta ligands (Dll1, Dll3, and Dll4) and two Serrate ligands (Jagged1 and Jagged2) present in mammals.<ref name="Introduction to Notch Signalling"/> The binding between the Notch receptor and the ligand on the adjacent cell induces the release of the Notch intracellular domain (NICD) via a sequence of proteolytic reactions.<ref name="The Developing Human"/> Cell-cell interaction is therefore critical in the process of triggering Notch signalling.<br />
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The interaction on the cell surface between Notch and its ligand on an adjacent cell causes the extracellular metalloprotease site (S2 site) to be exposed. The S2 site is then cleaved by transmembrane proteases belonging to the a disintegrin and metalloproteinase/tumour necrosis factor α converting enzyme (ADAM/TACE) family. The remaining Notch fragment subsequently undergoes two more intramembranous cleavages at the S3/S4 sites by the γ-secretase complex. Finally, the NICD is released and enters the nucleus to interacting with CSL (CBF1, Suppressor of Hairless, Lag-1). CSL is a DNA-binding protein that acts as a transcription factor by forming repressor or activator complexes that interact with Notch target genes.<ref name=PMID10075488/> To stop signalling, the NICD is phosphorylated by kinases and ubiquitinated by E3 ubiquitin ligases, which results in proteasome mediated degradation and subsequent termination of the signal.<ref name="Introduction to Notch Signalling"/><br />
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====Non-canonical pathway====<br />
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<br />
====Transcriptional regulation of Notch signalling====<br />
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===Roles in Embryonic Development===<br />
The phylogenetically conserved Notch signalling pathway plays a crucial role in the development of multiple organ systems, and is a major regulator of stem cell fate. It is responsible for the regulation of the transcription of a number of signalling molecules, such as ''MyoD'', ''Mash1'' and ''GATA2'', which are genes controlling the fate of myogenic, neurogenic and haematopoietic stem cells, respectively. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> The following subsections will further elucidate the vital roles of Notch signalling during normal embryonic development. <br />
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<br />
====Cardiovascular====<br />
'''Cardiomyocyte Specification and Differentiation'''<br />
<br />
Expression during the appropriate window of the timeline of embryogenesis of Notch receptors, ligands and downstream effector molecules elucidates a role for the Notch pathway in the earliest stages of cardiac development. It has been found to restrict the expression of specific cardiogenic genes in a spatiotemporal manner and regulate cardiac field specification as early as during gastrulation. <ref name=PMID19580804><pubmed>19580804</pubmed></ref> Interestingly, Notch has been found to play both suppressive and promoting roles in cardiogenesis.<br />
<br />
For example, it has been shown that Notch suppresses cardiomyocyte cell fate specification during early cardiogenesis. This has been demonstrated through studies such as that carried out by Rones and colleagues (2000), which used activation and inhibition of Notch signaling in Xenopus. <ref name=PMID10934030><pubmed>10934030</pubmed></ref><br />
<br />
On the other hand, studies such as that by Boni and colleagues (2008) have found that Notch signalling may also promote myogenesis from cardiac progenitor cells. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> Cardiogenesis has also been promoted by downregulating Notch-1 activity in stem cells of embryos (Nemir et al., 2006).<ref name=PMID16690879><pubmed>16690879</pubmed></ref><br />
<br />
Despite the understanding that Notch signalling is crucial to embryonic myogenesis, the exact molecular mechanism remains elusive. Research by Buas and colleagues (2010) has explored such mechanisms by studying the Notch target, Hey1, which is known to suppress myogenic differentiation. They concluded that this inhibitory function of Hey1 is primarily mediated through binding near to myogenin and Mef2C promoters, which leads to cessation of target gene expression. <ref name=PMID19917614><pubmed>19917614</pubmed></ref><br />
<br />
'''Development of the Atrioventricular Canal'''<br />
<br />
A study by Rutenberg and colleagues (2006) and another by Kokubo and colleagues (2007) implicate a role for Notch signaling in the region between the atria and the ventricles of the heart (the atrioventricular canal, or AVC).<ref name=PMID17021042><pubmed>17021042</pubmed></ref> <ref name=PMID17259303><pubmed>17259303</pubmed></ref> They used chicken and mouse models, respectively, to show that other signalling factors, ''Bmp2'' and ''Tbx2'', are restricted to the AVC region by Notch signalling during development. <br />
<br />
Furthermore, Watanabe and colleagues (2006) showed that deletion of Notch targets increases ''Bmp2'' expression and expansion of the AVC tissue, however other, non-Notch restrictive factors involved in AVC development are likely to exist.<ref name=PMID16554359><pubmed>16554359</pubmed></ref> <br />
<br />
See the summary diagram below for a schematic representation of this molecular interaction during AVC development.<br />
<br />
'''Heart Valve Development'''<br />
<br />
In order for the heart valve to properly form in the embryo, endocardial to mesenchymal transformation (EMT) must occur. The Notch pathway, alongside Wnt and Bmp, has been found to regulate the process of EMT, defects in which can lead to congenital heart valve disease. Interestingly, Timmerman and colleagues (2004) demonstrated that this role of Notch may also promote oncogenic transformation. This team also showed that embryos exhibited abortive endocardial EMT if they were deficient in Notch signalling components in vivo and in vitro. <ref name=PMID14701881><pubmed>14701881</pubmed></ref> <br />
<br />
A more recent paper by Wang and colleagues (2013) further explored the underlying signalling processes and interrelationships of molecules that impact EMT. They found that Jagged1-Notch1 signalling in cells of the endocardium potentiates expression of Wnt4, which in turn carries out paracrine action on adjacent AVC tissue to upregulate Bmp2 expression and thus signal EMT. <ref name=PMID23560082><pubmed>23560082</pubmed></ref><br />
<br />
'''Trabeculation'''<br />
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Trabeculation is the initial process of ventricular chamber development that forms a series of cardiomyocyte projections within the lumens of the ventricles of the heart (called trabeculae). Grego-Bessa and colleagues (2007) addressed the roles Notch plays in trabeculation through ''RBPJk'' (the gene product of which interacts with Notch) and ''Notch1'' gene manipulation. Mutants of these two genes showed perturbed expression and signalling of ''EphrinB2'', ''NRG1'' and ''BMP10'', alongside reduced proliferation of myocardiocytes. This research ultimately suggested that ''EphrinB2'' is a direct target of Notch in the endocardium that simultaneously requires the Notch-dependent action of BMP10 and NRG1 in order for ventricular myocardium proliferation and differentiation to occur normally. <ref name=PMID17336907><pubmed>17336907</pubmed></ref> Furthermore, the important process of trabeculation has recently been shown to be controlled by sequential Notch activation by an investigation by D’Amato and colleagues (2015). <ref name=PMID26641715><pubmed>26641715</pubmed></ref><br />
<br />
'''Development of the Outflow Tract'''<br />
<br />
TBC<br />
<br />
<br />
[[File:Summary Figure of Notch in Cardiac Development.jpeg|frame|center|alt=Summary of Notch Signalling in Cardiac Development|Summary of Notch Signalling in Cardiac Development<ref name=PMID24345875><pubmed>24345875</pubmed></ref>]]<br />
<br><br />
<br />
====Central Nervous System====<br />
'''Early Neural Differentiation'''<br />
<br />
Notch plays a major role in promoting neural commitment of cells. Lowell and colleagues (2011) used genetic manipulation to discover that the phenotype of stem cells is not affected by constitutively activated Notch in mouse embryonic stem cells (mESCs), however, interfering with Notch signalling -for example by pharmacological means- did impede neural fate determination. This role required Notch signalling via fibroblast growth factor (FGF) receptors. Furthermore, the conservation of the Notch signalling pathway within pluripotent stem cells is implied due to the existence of Notch ligands in stromal cells in human embryonic stem cells (hESCs) that induce neural differentiation. <ref name=PMID16594731><pubmed>16594731</pubmed></ref><br />
<br />
Das and colleagues (2010) manipulated Notch protein levels during specific stages of neural differentiation and found that if Notch signalling pathways were activated during day 3 of neural development for 6 hours, cell proliferation was dramatically enhanced. This was attributed to the induction by Notch of cyclin D1 expression. Without Notch signalling during neural development, there was reduced cyclin D1 levels. Manipulation of mESCs to express a dominant negative form of cyclin D1 resulted in abrogation of cell proliferation stimulated by Notch. Overall these results imply a temporally-specific role for Notch in CNS development, and that it requires cyclin D1 as a signalling molecule. <ref name=PMID20887720><pubmed>20887720</pubmed></ref><br />
<br><br><br />
<br />
====Other Systems====<br />
<br><br />
<br />
===Roles in Animal Development===<br />
====''Drosophila melanogaster''====<br />
Unlike the four Notch paralogs in humans, only one Notch homolog is present in ''Drosophila''.<ref name="Introduction to Notch Signalling"/><br />
<br />
Research has shown that Notch is crucial for the formation of longitudinal connections in the Drosophila CNS. Kuzina, Song, and Giniger (2011) created temperature-sensitive mutations of Notch genes that prevented the development of mature longitudinal axon tracts. They also found that the Notch phenotype appears at the earliest stages of the development of longitudinal connections in the CNS by observing early stage 13 embryos.<ref name=PMID21447553><pubmed>21447553</pubmed></ref><br />
<br><br><br />
<br />
====''Caenorhabditis elegans''====<br />
The Notch pathway in C. elegans occurs throughout development in populations of equipotent cells for neuronal function in postmitotic differentiated neurons. In these postmitotic neurons, there is a specialised post embryonic development stage knows as 'dauer'. The Notch pathway is activated when cell signalling downstream of the developmental decision enter dauer. The Notch receptor glp-1 and the ligand lag-2 are expressed in the dauer stage and aid in maintaining this stage. Another Notch receptor, lin-12, functions upstream of insulin signalling components to promote conditions for growth and enhance dauer recovery. <ref name=PMID18599512><pubmed>18599512</pubmed></ref><br />
<br><br><br />
<br />
====''Danio rerio''====<br />
<br><br />
<br />
===Abnormalities in Notch signalling===<br />
====Alagille syndrome====<br />
Alagille syndrome (AGS) is an autosomal dominant, multisystem disorder that mainly affects the liver, heart, and kidney. Diagnostic characteristics of the disease include liver disease, cardiac disease, vertebral defects, eye conditions, and facial features, as well as renal and vascular abnormalities.<ref><pubmed>26548814</pubmed></ref> In 94% of clinically diagnosed cases, a mutation in the gene encoding the Notch ligand JAG1 has been identified as a contributing factor. In combination with this, a mutation in the NOTCH2 gene has also been implicated in the manifestation of AGS in some patients.<ref><pubmed>16773578</pubmed></ref><br />
<br><br><br />
<br />
====Spondylocostal Dysostosis====<br />
Spondylocostal Dysostosis (SD) is a collective term for conditions characterised by anomalies relating to rib and spine. The vertebrae are fused and shaped abnormally which can result in scoliosis. Similarly, the ribs may also be fused together or in some cases completely missing. As a result, people with this condition have short trunk dwarfism where their bodies are short in stature but have normal length limbs. Genetic changes are known to cause SD. SD Type 1 is the most prevalent form of this disease which is caused by the mutation in the delta like canonical Notch ligand 3 (DLL3 gene).<ref><pubmed>10742114</pubmed></ref> DLL3 provides the information for making a protein that regulates the Notch signalling pathway. The DLL3 protein in conjunction with the Notch pathway is primarily responsible for preventing the fusion of future vertebrae in a process known as somite segmentation.<ref><pubmed>11236715</pubmed></ref> An interruption in the Notch pathway inhibits the somite segmentation resulting in abnormalities relating to the ribs and spine as seen in SD. 25 percent of SD arise from mutations in the identified genes and further research suggest that other genes involved in the Notch signalling pathway may also be related to SD.<br />
<br><br><br />
<br />
====Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)====<br />
CADASIL is an autosomal-dominant disease of the small to medium-sized arteries, mainly in the brain, that leads to dementia and disability in mid-life. The symptoms, age of onset, and prognosis are variable. Distinguishing symptoms include subcortical ischemic events (60-80% of cases), cognitive impairment (60% of late stage disease), migraines (30-40%), mood disturbances (30%), and apathy (40%).<ref name="PMID21045164"><pubmed>21045164</pubmed></ref><ref name="PMID20301673"><pubmed>20301673</pubmed></ref> Approximately 5-10% of CADASIL patients also experience seizures. The mean age of onset is 45 years of age and the disease duration is between 10–40 years. More than 95% of CADASIL cases present with pathogenic mutations in NOTCH3 (located on chromosome 19p13), specifically the epidermal growth factor-like repeat domain.<ref name="PMID20301673"/><ref><pubmed>24579972</pubmed></ref> The NOTCH3 gene is involved in the normal development of blood vessels in both fetal and adult brains. In adults, NOTCH3 is expressed in the smooth muscle cells of arteries.<ref name="PMID21045164"/> There is currently no effective treatment available for CADASIL.<br />
<br><br><br />
<br />
====Congenital Heart Defects====<br />
<br><br><br />
<br />
===Current Areas of Research===<br />
<br><br />
<br />
===Glossary===<br />
{| class="pretty table"<br />
| '''Gastrulation'''<br />
| Describes the formative process of the formation of the trilaminar embryo containing the three germ layers.<ref name="The Developing Human"/><br />
|-<br />
|}<br />
<br />
===References===<br />
<references/></div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=2016_Group_Project_2&diff=249142
2016 Group Project 2
2016-10-02T01:52:08Z
<p>Z5014803: /* Abnormalities in Notch signalling */</p>
<hr />
<div>{{ANAT2341Project2016header}}<br />
{{Group Assessment Criteria table}}<br />
<!-- Do not delete the above template from the Group project page. --><br />
<br />
==Notch signalling pathway==<br />
===Introduction===<br />
The Notch signalling pathway is the most prevalent form of intracellular communication in multicellular organism. The pathway is critical for cell differentiation, proliferation, and apoptosis. It is involved in embryonic organ development through the regulation of cell-cell signalling; specifically lateral inhibition, formation of boundaries, and cell lineage assignation.<ref name="The Developing Human">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2015). The developing human: clinically oriented embryology (10th ed.). Philadelphia: Saunders.</ref><ref name=PMID10075488><pubmed>10075488</pubmed></ref> This pathway is also actively involved in adjacent cell communication, developmental process such as adult homeostasis and stem cell maintenance. Since this pathway is an intricate and crucial aspect of an organisms development and cell signalling, a mutation in the functional components of this pathway can cause a myriad of diseases such as congenital disorders, cancers, strokes, Alagille syndrome and leukoencephalopathy. <ref name=PMID19255248><pubmed>19255248</pubmed></ref> The Notch signalling process primarily utilises a ligand- receptor interaction to release protein fragments at the cellular membrane that provide signals to the internal aspect of the cell and to the adjacent cells. In mammals the Notch signalling pathway is comprised of 4 receptors (Notch 1-4) which are bounded by the Delta and Jagged ligands that bring about the activation of this pathway. <br />
<br><br><br />
<br />
===History===<br />
{| class="pretty table"<br />
| 1914<br />
| First description of a "notch" defect (loss of tissue in the wing) in ''Drosophila'' by John S. Dexter, giving the gene its name<br />
|-<br />
| 1917<br />
| First allele of ''Notch'' is identified by Thomas Hunt Morgan<br />
|-<br />
| 1930s<br />
| Donald F. Poulson conducts research into the involvement of ''Notch'' in development<br />
|-<br />
| 1958<br />
| An investigation by W.J. Welshons confirmed that the locus of Notch is contained within the 3C7 band of the X chromosome.<br />
|-<br />
| 1983<br />
| DNA sequences belonging to the Notch locus cloned and determined that RNA is required for the function of the wild type Notch. Further insight developed into the function of Notch and its role in differentiation and regeneration.<br />
|-<br />
| 1986<br />
| The molecular analysis and sequence of the Notch locus was determined by Michael W Young and his team. A relationship was identified between the protein encoded by the major Notch transcript and mammalian clotting and growth factors <br />
|-<br />
| 1989<br />
| Neurogenic loci "Delta" and "Mastermind" identified and research conducted to search for genes which may have an interaction with the Notch protein. It was confirmed that mutations in these loci will affect neurogenesis.<br />
|}<br />
<br />
===Overview of Molecular Mechanisms===<br />
Mammals possess a total of four ''Notch'' genes, with five genes for encoding the associated ligands, Delta-like and Jagged. The ''Notch'' genes each code for a single transmembrane receptor. Extracellularly, it contains epidermal growth factor (EGF)-like repeats for ligand interaction and Lin-12-Notch (LN) repeats for regulating the interactions between the extracellular and intracellular regions. Intracellularly, Notch has seven ankyrin (ANK) repeats and a transactivation domain (TAD), as well as a proline, glutamine, serine, threonine-rich (PEST) domain for degradation of Notch.<br />
<br><br><br />
====Canonical pathway====<br />
[[File:Overview of Notch signalling.png|thumb|500px|Summary of canonical Notch signalling<ref><pubmed>27404588</pubmed></ref>]]<br />
The canonical Notch pathway is unique in that it involves direct interaction between adjacent cells, as opposed to paracrine signalling, because both the Notch ligands and Notch receptors are transmembrane proteins found in the cell membrane. Furthermore, the lack of a secondary messenger or amplification process means that the Notch pathway has limited opportunities for regulation and must therefore be tightly controlled. Depending on its developmental and cellular context, activation or inhibition of the pathway can result in a variety of cellular responses, including cell death, proliferation, or differentiation.<ref name="Introduction to Notch Signalling">Yamamoto, S., Schulze, K.L. & Bellen, H.J. (2014). Introduction to Notch Signalling. ''Notch Signaling: Methods and Protocols''. Methods in Molecular Biology: 1187</ref><br />
<br><br><br />
Four Notch proteins are involved in the canonical pathway. NOTCH1 to NOTCH4 are single transmembrane receptors and can interact with a variety of ligands, including NOTCH ligands (e.g. Delta ligands) and Serrate ligands. There are three Delta ligands (Dll1, Dll3, and Dll4) and two Serrate ligands (Jagged1 and Jagged2) present in mammals.<ref name="Introduction to Notch Signalling"/> The binding between the Notch receptor and the ligand on the adjacent cell induces the release of the Notch intracellular domain (NICD) via a sequence of proteolytic reactions.<ref name="The Developing Human"/> Cell-cell interaction is therefore critical in the process of triggering Notch signalling.<br />
<br><br><br />
The interaction on the cell surface between Notch and its ligand on an adjacent cell causes the extracellular metalloprotease site (S2 site) to be exposed. The S2 site is then cleaved by transmembrane proteases belonging to the a disintegrin and metalloproteinase/tumour necrosis factor α converting enzyme (ADAM/TACE) family. The remaining Notch fragment subsequently undergoes two more intramembranous cleavages at the S3/S4 sites by the γ-secretase complex. Finally, the NICD is released and enters the nucleus to interacting with CSL (CBF1, Suppressor of Hairless, Lag-1). CSL is a DNA-binding protein that acts as a transcription factor by forming repressor or activator complexes that interact with Notch target genes.<ref name=PMID10075488/> To stop signalling, the NICD is phosphorylated by kinases and ubiquitinated by E3 ubiquitin ligases, which results in proteasome mediated degradation and subsequent termination of the signal.<ref name="Introduction to Notch Signalling"/><br />
<br><br><br />
====Non-canonical pathway====<br />
<br><br />
<br />
====Transcriptional regulation of Notch signalling====<br />
<br><br />
<br />
===Roles in Embryonic Development===<br />
The phylogenetically conserved Notch signalling pathway plays a crucial role in the development of multiple organ systems, and is a major regulator of stem cell fate. It is responsible for the regulation of the transcription of a number of signalling molecules, such as ''MyoD'', ''Mash1'' and ''GATA2'', which are genes controlling the fate of myogenic, neurogenic and haematopoietic stem cells, respectively. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> The following subsections will further elucidate the vital roles of Notch signalling during normal embryonic development. <br />
<br><br><br />
<br />
====Cardiovascular====<br />
'''Cardiomyocyte Specification and Differentiation'''<br />
<br />
Expression during the appropriate window of the timeline of embryogenesis of Notch receptors, ligands and downstream effector molecules elucidates a role for the Notch pathway in the earliest stages of cardiac development. It has been found to restrict the expression of specific cardiogenic genes in a spatiotemporal manner and regulate cardiac field specification as early as during gastrulation. <ref name=PMID19580804><pubmed>19580804</pubmed></ref> Interestingly, Notch has been found to play both suppressive and promoting roles in cardiogenesis.<br />
<br />
For example, it has been shown that Notch suppresses cardiomyocyte cell fate specification during early cardiogenesis. This has been demonstrated through studies such as that carried out by Rones and colleagues (2000), which used activation and inhibition of Notch signaling in Xenopus. <ref name=PMID10934030><pubmed>10934030</pubmed></ref><br />
<br />
On the other hand, studies such as that by Boni and colleagues (2008) have found that Notch signalling may also promote myogenesis from cardiac progenitor cells. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> Cardiogenesis has also been promoted by downregulating Notch-1 activity in stem cells of embryos (Nemir et al., 2006).<ref name=PMID16690879><pubmed>16690879</pubmed></ref><br />
<br />
Despite the understanding that Notch signalling is crucial to embryonic myogenesis, the exact molecular mechanism remains elusive. Research by Buas and colleagues (2010) has explored such mechanisms by studying the Notch target, Hey1, which is known to suppress myogenic differentiation. They concluded that this inhibitory function of Hey1 is primarily mediated through binding near to myogenin and Mef2C promoters, which leads to cessation of target gene expression. <ref name=PMID19917614><pubmed>19917614</pubmed></ref><br />
<br />
'''Development of the Atrioventricular Canal'''<br />
<br />
A study by Rutenberg and colleagues (2006) and another by Kokubo and colleagues (2007) implicate a role for Notch signaling in the region between the atria and the ventricles of the heart (the atrioventricular canal, or AVC).<ref name=PMID17021042><pubmed>17021042</pubmed></ref> <ref name=PMID17259303><pubmed>17259303</pubmed></ref> They used chicken and mouse models, respectively, to show that other signalling factors, ''Bmp2'' and ''Tbx2'', are restricted to the AVC region by Notch signalling during development. <br />
<br />
Furthermore, Watanabe and colleagues (2006) showed that deletion of Notch targets increases ''Bmp2'' expression and expansion of the AVC tissue, however other, non-Notch restrictive factors involved in AVC development are likely to exist.<ref name=PMID16554359><pubmed>16554359</pubmed></ref> <br />
<br />
See the summary diagram below for a schematic representation of this molecular interaction during AVC development.<br />
<br />
'''Heart Valve Development'''<br />
<br />
In order for the heart valve to properly form in the embryo, endocardial to mesenchymal transformation (EMT) must occur. The Notch pathway, alongside Wnt and Bmp, has been found to regulate the process of EMT, defects in which can lead to congenital heart valve disease. Interestingly, Timmerman and colleagues (2004) demonstrated that this role of Notch may also promote oncogenic transformation. This team also showed that embryos exhibited abortive endocardial EMT if they were deficient in Notch signalling components in vivo and in vitro. <ref name=PMID14701881><pubmed>14701881</pubmed></ref> <br />
<br />
A more recent paper by Wang and colleagues (2013) further explored the underlying signalling processes and interrelationships of molecules that impact EMT. They found that Jagged1-Notch1 signalling in cells of the endocardium potentiates expression of Wnt4, which in turn carries out paracrine action on adjacent AVC tissue to upregulate Bmp2 expression and thus signal EMT. <ref name=PMID23560082><pubmed>23560082</pubmed></ref><br />
<br />
'''Trabeculation'''<br />
<br />
Trabeculation is the initial process of ventricular chamber development that forms a series of cardiomyocyte projections within the lumens of the ventricles of the heart (called trabeculae). Grego-Bessa and colleagues (2007) addressed the roles Notch plays in trabeculation through ''RBPJk'' (the gene product of which interacts with Notch) and ''Notch1'' gene manipulation. Mutants of these two genes showed perturbed expression and signalling of ''EphrinB2'', ''NRG1'' and ''BMP10'', alongside reduced proliferation of myocardiocytes. This research ultimately suggested that ''EphrinB2'' is a direct target of Notch in the endocardium that simultaneously requires the Notch-dependent action of BMP10 and NRG1 in order for ventricular myocardium proliferation and differentiation to occur normally. <ref name=PMID17336907><pubmed>17336907</pubmed></ref> Furthermore, the important process of trabeculation has recently been shown to be controlled by sequential Notch activation by an investigation by D’Amato and colleagues (2015). <ref name=PMID26641715><pubmed>26641715</pubmed></ref><br />
<br />
'''Development of the Outflow Tract'''<br />
<br />
TBC<br />
<br />
<br />
[[File:Summary Figure of Notch in Cardiac Development.jpeg|frame|center|alt=Summary of Notch Signalling in Cardiac Development|Summary of Notch Signalling in Cardiac Development<ref name=PMID24345875><pubmed>24345875</pubmed></ref>]]<br />
<br><br />
<br />
====Central Nervous System====<br />
'''Early Neural Differentiation'''<br />
<br />
Notch plays a major role in promoting neural commitment of cells. Lowell and colleagues (2011) used genetic manipulation to discover that the phenotype of stem cells is not affected by constitutively activated Notch in mouse embryonic stem cells (mESCs), however, interfering with Notch signalling -for example by pharmacological means- did impede neural fate determination. This role required Notch signalling via fibroblast growth factor (FGF) receptors. Furthermore, the conservation of the Notch signalling pathway within pluripotent stem cells is implied due to the existence of Notch ligands in stromal cells in human embryonic stem cells (hESCs) that induce neural differentiation. <ref name=PMID16594731><pubmed>16594731</pubmed></ref><br />
<br />
Das and colleagues (2010) manipulated Notch protein levels during specific stages of neural differentiation and found that if Notch signalling pathways were activated during day 3 of neural development for 6 hours, cell proliferation was dramatically enhanced. This was attributed to the induction by Notch of cyclin D1 expression. Without Notch signalling during neural development, there was reduced cyclin D1 levels. Manipulation of mESCs to express a dominant negative form of cyclin D1 resulted in abrogation of cell proliferation stimulated by Notch. Overall these results imply a temporally-specific role for Notch in CNS development, and that it requires cyclin D1 as a signalling molecule. <ref name=PMID20887720><pubmed>20887720</pubmed></ref><br />
<br><br><br />
<br />
====Other Systems====<br />
<br><br />
<br />
===Roles in Animal Development===<br />
====''Drosophila melanogaster''====<br />
Unlike the four Notch paralogs in humans, only one Notch homolog is present in ''Drosophila''.<ref name="Introduction to Notch Signalling"/><br />
<br />
Research has shown that Notch is crucial for the formation of longitudinal connections in the Drosophila CNS. Kuzina, Song, and Giniger (2011) created temperature-sensitive mutations of Notch genes that prevented the development of mature longitudinal axon tracts. They also found that the Notch phenotype appears at the earliest stages of the development of longitudinal connections in the CNS by observing early stage 13 embryos.<ref name=PMID21447553><pubmed>21447553</pubmed></ref><br />
<br><br><br />
<br />
====''Caenorhabditis elegans''====<br />
<br><br />
<br />
====''Danio rerio''====<br />
<br><br />
<br />
===Abnormalities in Notch signalling===<br />
====Alagille syndrome====<br />
Alagille syndrome (AGS) is an autosomal dominant, multisystem disorder that mainly affects the liver, heart, and kidney. Diagnostic characteristics of the disease include liver disease, cardiac disease, vertebral defects, eye conditions, and facial features, as well as renal and vascular abnormalities.<ref><pubmed>26548814</pubmed></ref> In 94% of clinically diagnosed cases, a mutation in the gene encoding the Notch ligand JAG1 has been identified as a contributing factor. In combination with this, a mutation in the NOTCH2 gene has also been implicated in the manifestation of AGS in some patients.<ref><pubmed>16773578</pubmed></ref><br />
<br><br><br />
<br />
====Spondylocostal Dysostosis====<br />
Spondylocostal Dysostosis (SD) is a collective term for conditions characterised by anomalies relating to rib and spine. The vertebrae are fused and shaped abnormally which can result in scoliosis. Similarly, the ribs may also be fused together or in some cases completely missing. As a result, people with this condition have short trunk dwarfism where their bodies are short in stature but have normal length limbs. Genetic changes are known to cause SD. SD Type 1 is the most prevalent form of this disease which is caused by the mutation in the delta like canonical Notch ligand 3 (DLL3 gene).<ref><pubmed>10742114</pubmed></ref> DLL3 provides the information for making a protein that regulates the Notch signalling pathway. The DLL3 protein in conjunction with the Notch pathway is primarily responsible for preventing the fusion of future vertebrae in a process known as somite segmentation.<ref><pubmed>11236715</pubmed></ref> An interruption in the Notch pathway inhibits the somite segmentation resulting in abnormalities relating to the ribs and spine as seen in SD. 25 percent of SD arise from mutations in the identified genes and further research suggest that other genes involved in the Notch signalling pathway may also be related to SD.<br />
<br><br><br />
<br />
====Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)====<br />
CADASIL is an autosomal-dominant disease of the small to medium-sized arteries, mainly in the brain, that leads to dementia and disability in mid-life. The symptoms, age of onset, and prognosis are variable. Distinguishing symptoms include subcortical ischemic events (60-80% of cases), cognitive impairment (60% of late stage disease), migraines (30-40%), mood disturbances (30%), and apathy (40%).<ref name="PMID21045164"><pubmed>21045164</pubmed></ref><ref name="PMID20301673"><pubmed>20301673</pubmed></ref> Approximately 5-10% of CADASIL patients also experience seizures. The mean age of onset is 45 years of age and the disease duration is between 10–40 years. More than 95% of CADASIL cases present with pathogenic mutations in NOTCH3 (located on chromosome 19p13), specifically the epidermal growth factor-like repeat domain.<ref name="PMID20301673"/><ref><pubmed>24579972</pubmed></ref> The NOTCH3 gene is involved in the normal development of blood vessels in both fetal and adult brains. In adults, NOTCH3 is expressed in the smooth muscle cells of arteries.<ref name="PMID21045164"/> There is currently no effective treatment available for CADASIL.<br />
<br><br><br />
<br />
====Congenital Heart Defects====<br />
<br><br><br />
<br />
===Current Areas of Research===<br />
<br><br />
<br />
===Glossary===<br />
{| class="pretty table"<br />
| '''Gastrulation'''<br />
| Describes the formative process of the formation of the trilaminar embryo containing the three germ layers.<ref name="The Developing Human"/><br />
|-<br />
|}<br />
<br />
===References===<br />
<references/></div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=2016_Group_Project_2&diff=249138
2016 Group Project 2
2016-10-02T00:15:12Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016header}}<br />
{{Group Assessment Criteria table}}<br />
<!-- Do not delete the above template from the Group project page. --><br />
<br />
==Notch signalling pathway==<br />
===Introduction===<br />
The Notch signalling pathway is the most prevalent form of intracellular communication in multicellular organism. The pathway is critical for cell differentiation, proliferation, and apoptosis. It is involved in embryonic organ development through the regulation of cell-cell signalling; specifically lateral inhibition, formation of boundaries, and cell lineage assignation.<ref name="The Developing Human">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2015). The developing human: clinically oriented embryology (10th ed.). Philadelphia: Saunders.</ref><ref name=PMID10075488><pubmed>10075488</pubmed></ref> This pathway is also actively involved in adjacent cell communication, developmental process such as adult homeostasis and stem cell maintenance. Since this pathway is an intricate and crucial aspect of an organisms development and cell signalling, a mutation in the functional components of this pathway can cause a myriad of diseases such as congenital disorders, cancers, strokes, Alagille syndrome and leukoencephalopathy. <ref name=PMID19255248><pubmed>19255248</pubmed></ref> The Notch signalling process primarily utilises a ligand- receptor interaction to release protein fragments at the cellular membrane that provide signals to the internal aspect of the cell and to the adjacent cells. In mammals the Notch signalling pathway is comprised of 4 receptors (Notch 1-4) which are bounded by the Delta and Jagged ligands that bring about the activation of this pathway. <br />
<br><br><br />
<br />
===History===<br />
{| class="pretty table"<br />
| 1914<br />
| First description of a "notch" defect (loss of tissue in the wing) in ''Drosophila'' by John S. Dexter, giving the gene its name<br />
|-<br />
| 1917<br />
| First allele of ''Notch'' is identified by Thomas Hunt Morgan<br />
|-<br />
| 1930s<br />
| Donald F. Poulson conducts research into the involvement of ''Notch'' in development<br />
|-<br />
| 1958<br />
| An investigation by W.J. Welshons confirmed that the locus of Notch is contained within the 3C7 band of the X chromosome.<br />
|-<br />
| 1983<br />
| DNA sequences belonging to the Notch locus cloned and determined that RNA is required for the function of the wild type Notch. Further insight developed into the function of Notch and its role in differentiation and regeneration.<br />
|-<br />
| 1986<br />
| The molecular analysis and sequence of the Notch locus was determined by Michael W Young and his team. A relationship was identified between the protein encoded by the major Notch transcript and mammalian clotting and growth factors <br />
|-<br />
| 1989<br />
| Neurogenic loci "Delta" and "Mastermind" identified and research conducted to search for genes which may have an interaction with the Notch protein. It was confirmed that mutations in these loci will affect neurogenesis.<br />
|}<br />
<br />
===Overview of Molecular Mechanisms===<br />
Mammals possess a total of four ''Notch'' genes, with five genes for encoding the associated ligands, Delta-like and Jagged. The ''Notch'' genes each code for a single transmembrane receptor. Extracellularly, it contains epidermal growth factor (EGF)-like repeats for ligand interaction and Lin-12-Notch (LN) repeats for regulating the interactions between the extracellular and intracellular regions. Intracellularly, Notch has seven ankyrin (ANK) repeats and a transactivation domain (TAD), as well as a proline, glutamine, serine, threonine-rich (PEST) domain for degradation of Notch.<br />
<br><br><br />
====Canonical pathway====<br />
[[File:Overview of Notch signalling.png|thumb|500px|Summary of canonical Notch signalling<ref><pubmed>27404588</pubmed></ref>]]<br />
The canonical Notch pathway is unique in that it involves direct interaction between adjacent cells, as opposed to paracrine signalling, because both the Notch ligands and Notch receptors are transmembrane proteins found in the cell membrane. Furthermore, the lack of a secondary messenger or amplification process means that the Notch pathway has limited opportunities for regulation and must therefore be tightly controlled. Depending on its developmental and cellular context, activation or inhibition of the pathway can result in a variety of cellular responses, including cell death, proliferation, or differentiation.<ref name="Introduction to Notch Signalling">Yamamoto, S., Schulze, K.L. & Bellen, H.J. (2014). Introduction to Notch Signalling. ''Notch Signaling: Methods and Protocols''. Methods in Molecular Biology: 1187</ref><br />
<br><br><br />
Four Notch proteins are involved in the canonical pathway. NOTCH1 to NOTCH4 are single transmembrane receptors and can interact with a variety of ligands, including NOTCH ligands (e.g. Delta ligands) and Serrate ligands. There are three Delta ligands (Dll1, Dll3, and Dll4) and two Serrate ligands (Jagged1 and Jagged2) present in mammals.<ref name="Introduction to Notch Signalling"/> The binding between the Notch receptor and the ligand on the adjacent cell induces the release of the Notch intracellular domain (NICD) via a sequence of proteolytic reactions.<ref name="The Developing Human"/> Cell-cell interaction is therefore critical in the process of triggering Notch signalling.<br />
<br><br><br />
The interaction on the cell surface between Notch and its ligand on an adjacent cell causes the extracellular metalloprotease site (S2 site) to be exposed. The S2 site is then cleaved by transmembrane proteases belonging to the a disintegrin and metalloproteinase/tumour necrosis factor α converting enzyme (ADAM/TACE) family. The remaining Notch fragment subsequently undergoes two more intramembranous cleavages at the S3/S4 sites by the γ-secretase complex. Finally, the NICD is released and enters the nucleus to interacting with CSL (CBF1, Suppressor of Hairless, Lag-1). CSL is a DNA-binding protein that acts as a transcription factor by forming repressor or activator complexes that interact with Notch target genes.<ref name=PMID10075488/> To stop signalling, the NICD is phosphorylated by kinases and ubiquitinated by E3 ubiquitin ligases, which results in proteasome mediated degradation and subsequent termination of the signal.<ref name="Introduction to Notch Signalling"/><br />
<br><br><br />
====Non-canonical pathway====<br />
<br><br />
<br />
====Transcriptional regulation of Notch signalling====<br />
<br><br />
<br />
===Roles in Embryonic Development===<br />
The phylogenetically conserved Notch signalling pathway plays a crucial role in the development of multiple organ systems, and is a major regulator of stem cell fate. It is responsible for the regulation of the transcription of a number of signalling molecules, such as ''MyoD'', ''Mash1'' and ''GATA2'', which are genes controlling the fate of myogenic, neurogenic and haematopoietic stem cells, respectively. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> The following subsections will further elucidate the vital roles of Notch signalling during normal embryonic development. <br />
<br><br><br />
<br />
====Cardiovascular====<br />
'''Cardiomyocyte Specification and Differentiation'''<br />
<br />
Expression during the appropriate window of the timeline of embryogenesis of Notch receptors, ligands and downstream effector molecules elucidates a role for the Notch pathway in the earliest stages of cardiac development. It has been found to restrict the expression of specific cardiogenic genes in a spatiotemporal manner and regulate cardiac field specification as early as during gastrulation. <ref name=PMID19580804><pubmed>19580804</pubmed></ref> Interestingly, Notch has been found to play both suppressive and promoting roles in cardiogenesis.<br />
<br />
For example, it has been shown that Notch suppresses cardiomyocyte cell fate specification during early cardiogenesis. This has been demonstrated through studies such as that carried out by Rones and colleagues (2000), which used activation and inhibition of Notch signaling in Xenopus. <ref name=PMID10934030><pubmed>10934030</pubmed></ref><br />
<br />
On the other hand, studies such as that by Boni and colleagues (2008) have found that Notch signalling may also promote myogenesis from cardiac progenitor cells. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> Cardiogenesis has also been promoted by downregulating Notch-1 activity in stem cells of embryos (Nemir et al., 2006).<ref name=PMID16690879><pubmed>16690879</pubmed></ref><br />
<br />
Despite the understanding that Notch signalling is crucial to embryonic myogenesis, the exact molecular mechanism remains elusive. Research by Buas and colleagues (2010) has explored such mechanisms by studying the Notch target, Hey1, which is known to suppress myogenic differentiation. They concluded that this inhibitory function of Hey1 is primarily mediated through binding near to myogenin and Mef2C promoters, which leads to cessation of target gene expression. <ref name=PMID19917614><pubmed>19917614</pubmed></ref><br />
<br />
'''Development of the Atrioventricular Canal'''<br />
<br />
A study by Rutenberg and colleagues (2006) and another by Kokubo and colleagues (2007) implicate a role for Notch signaling in the region between the atria and the ventricles of the heart (the atrioventricular canal, or AVC).<ref name=PMID17021042><pubmed>17021042</pubmed></ref> <ref name=PMID17259303><pubmed>17259303</pubmed></ref> They used chicken and mouse models, respectively, to show that other signalling factors, ''Bmp2'' and ''Tbx2'', are restricted to the AVC region by Notch signalling during development. <br />
<br />
Furthermore, Watanabe and colleagues (2006) showed that deletion of Notch targets increases ''Bmp2'' expression and expansion of the AVC tissue, however other, non-Notch restrictive factors involved in AVC development are likely to exist.<ref name=PMID16554359><pubmed>16554359</pubmed></ref> <br />
<br />
See the summary diagram below for a schematic representation of this molecular interaction during AVC development.<br />
<br />
'''Heart Valve Development'''<br />
<br />
In order for the heart valve to properly form in the embryo, endocardial to mesenchymal transformation (EMT) must occur. The Notch pathway, alongside Wnt and Bmp, has been found to regulate the process of EMT, defects in which can lead to congenital heart valve disease. Interestingly, Timmerman and colleagues (2004) demonstrated that this role of Notch may also promote oncogenic transformation. This team also showed that embryos exhibited abortive endocardial EMT if they were deficient in Notch signalling components in vivo and in vitro. <ref name=PMID14701881><pubmed>14701881</pubmed></ref> <br />
<br />
A more recent paper by Wang and colleagues (2013) further explored the underlying signalling processes and interrelationships of molecules that impact EMT. They found that Jagged1-Notch1 signalling in cells of the endocardium potentiates expression of Wnt4, which in turn carries out paracrine action on adjacent AVC tissue to upregulate Bmp2 expression and thus signal EMT. <ref name=PMID23560082><pubmed>23560082</pubmed></ref><br />
<br />
'''Trabeculation'''<br />
<br />
Trabeculation is the initial process of ventricular chamber development that forms a series of cardiomyocyte projections within the lumens of the ventricles of the heart (called trabeculae). Grego-Bessa and colleagues (2007) addressed the roles Notch plays in trabeculation through ''RBPJk'' (the gene product of which interacts with Notch) and ''Notch1'' gene manipulation. Mutants of these two genes showed perturbed expression and signalling of ''EphrinB2'', ''NRG1'' and ''BMP10'', alongside reduced proliferation of myocardiocytes. This research ultimately suggested that ''EphrinB2'' is a direct target of Notch in the endocardium that simultaneously requires the Notch-dependent action of BMP10 and NRG1 in order for ventricular myocardium proliferation and differentiation to occur normally. <ref name=PMID17336907><pubmed>17336907</pubmed></ref> Furthermore, the important process of trabeculation has recently been shown to be controlled by sequential Notch activation by an investigation by D’Amato and colleagues (2015). <ref name=PMID26641715><pubmed>26641715</pubmed></ref><br />
<br />
'''Development of the Outflow Tract'''<br />
<br />
TBC<br />
<br />
<br />
[[File:Summary Figure of Notch in Cardiac Development.jpeg|frame|center|alt=Summary of Notch Signalling in Cardiac Development|Summary of Notch Signalling in Cardiac Development<ref name=PMID24345875><pubmed>24345875</pubmed></ref>]]<br />
<br><br />
<br />
====Central Nervous System====<br />
'''Early Neural Differentiation'''<br />
<br />
Notch plays a major role in promoting neural commitment of cells. Lowell and colleagues (2011) used genetic manipulation to discover that the phenotype of stem cells is not affected by constitutively activated Notch in mouse embryonic stem cells (mESCs), however, interfering with Notch signalling -for example by pharmacological means- did impede neural fate determination. This role required Notch signalling via fibroblast growth factor (FGF) receptors. Furthermore, the conservation of the Notch signalling pathway within pluripotent stem cells is implied due to the existence of Notch ligands in stromal cells in human embryonic stem cells (hESCs) that induce neural differentiation. <ref name=PMID16594731><pubmed>16594731</pubmed></ref><br />
<br />
Das and colleagues (2010) manipulated Notch protein levels during specific stages of neural differentiation and found that if Notch signalling pathways were activated during day 3 of neural development for 6 hours, cell proliferation was dramatically enhanced. This was attributed to the induction by Notch of cyclin D1 expression. Without Notch signalling during neural development, there was reduced cyclin D1 levels. Manipulation of mESCs to express a dominant negative form of cyclin D1 resulted in abrogation of cell proliferation stimulated by Notch. Overall these results imply a temporally-specific role for Notch in CNS development, and that it requires cyclin D1 as a signalling molecule. <ref name=PMID20887720><pubmed>20887720</pubmed></ref><br />
<br><br><br />
<br />
====Other Systems====<br />
<br><br />
<br />
===Roles in Animal Development===<br />
====''Drosophila melanogaster''====<br />
Unlike the four Notch paralogs in humans, only one Notch homolog is present in ''Drosophila''.<ref name="Introduction to Notch Signalling"/><br />
<br />
Research has shown that Notch is crucial for the formation of longitudinal connections in the Drosophila CNS. Kuzina, Song, and Giniger (2011) created temperature-sensitive mutations of Notch genes that prevented the development of mature longitudinal axon tracts. They also found that the Notch phenotype appears at the earliest stages of the development of longitudinal connections in the CNS by observing early stage 13 embryos.<ref name=PMID21447553><pubmed>21447553</pubmed></ref><br />
<br><br><br />
<br />
====''Caenorhabditis elegans''====<br />
<br><br />
<br />
====''Danio rerio''====<br />
<br><br />
<br />
===Abnormalities in Notch signalling===<br />
====Alagille syndrome====<br />
Alagille syndrome (AGS) is an autosomal dominant, multisystem disorder that mainly affects the liver, heart, and kidney. Diagnostic characteristics of the disease include liver disease, cardiac disease, vertebral defects, eye conditions, and facial features, as well as renal and vascular abnormalities.<ref><pubmed>26548814</pubmed></ref> In 94% of clinically diagnosed cases, a mutation in the gene encoding the Notch ligand JAG1 has been identified as a contributing factor. In combination with this, a mutation in the NOTCH2 gene has also been implicated in the manifestation of AGS in some patients.<ref><pubmed>16773578</pubmed></ref><br />
<br><br><br />
<br />
====Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)====<br />
CADASIL is an autosomal-dominant disease of the small to medium-sized arteries, mainly in the brain, that leads to dementia and disability in mid-life. The symptoms, age of onset, and prognosis are variable. Distinguishing symptoms include subcortical ischemic events (60-80% of cases), cognitive impairment (60% of late stage disease), migraines (30-40%), mood disturbances (30%), and apathy (40%).<ref name="PMID21045164"><pubmed>21045164</pubmed></ref><ref name="PMID20301673"><pubmed>20301673</pubmed></ref> Approximately 5-10% of CADASIL patients also experience seizures. The mean age of onset is 45 years of age and the disease duration is between 10–40 years. More than 95% of CADASIL cases present with pathogenic mutations in NOTCH3 (located on chromosome 19p13), specifically the epidermal growth factor-like repeat domain.<ref name="PMID20301673"/><ref><pubmed>24579972</pubmed></ref> The NOTCH3 gene is involved in the normal development of blood vessels in both fetal and adult brains. In adults, NOTCH3 is expressed in the smooth muscle cells of arteries.<ref name="PMID21045164"/> There is currently no effective treatment available for CADASIL.<br />
<br><br><br />
<br />
====Congenital Heart Defects====<br />
<br><br><br />
<br />
===Current Areas of Research===<br />
<br><br />
<br />
===Glossary===<br />
{| class="pretty table"<br />
| '''Gastrulation'''<br />
| Describes the formative process of the formation of the trilaminar embryo containing the three germ layers.<ref name="The Developing Human"/><br />
|-<br />
|}<br />
<br />
===References===<br />
<references/></div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=2016_Group_Project_2&diff=248896
2016 Group Project 2
2016-09-26T00:56:50Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016header}}<br />
{{Group Assessment Criteria table}}<br />
<!-- Do not delete the above template from the Group project page. --><br />
<br />
==Notch signalling pathway==<br />
===Introduction===<br />
The Notch signalling pathway is the most prevalent form of intracellular communication in multicellular organism. The pathway is critical for cell differentiation, proliferation, and apoptosis. It is involved in embryonic organ development through the regulation of cell-cell signalling; specifically lateral inhibition, formation of boundaries, and cell lineage assignation.<ref name="The Developing Human">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2015). The developing human: clinically oriented embryology (10th ed.). Philadelphia: Saunders.</ref><ref name=PMID10075488><pubmed>10075488</pubmed></ref> This pathway is also actively involved in adjacent cell communication, developmental process such as adult homeostasis and stem cell maintenance. Since this pathway is an intricate and crucial aspect of an organisms development and cell signalling, a mutation in the functional components of this pathway can cause a myriad of diseases such as congenital disorders, cancers, strokes, Alagille syndrome and leukoencephalopathy. <ref name=PMID19255248><pubmed>19255248</pubmed></ref> The Notch signalling process primarily utilises a ligand- receptor interaction to release protein fragments at the cellular membrane that provide signals to the internal aspect of the cell and to the adjacent cells. In mammals the Notch signalling pathway is comprised of 4 receptors (Notch 1-4) which are bounded by the Delta and Jagged ligands that bring about the activation of this pathway. <br />
<br><br><br />
<br />
===History===<br />
{| class="pretty table"<br />
| 1914<br />
| First description of a "notch" defect (loss of tissue in the wing) in ''Drosophila'' by John S. Dexter, giving the gene its name<br />
|-<br />
| 1917<br />
| First allele of ''Notch'' is identified by Thomas Hunt Morgan<br />
|-<br />
| 1930s<br />
| Donald F. Poulson conducts research into the involvement of ''Notch'' in development<br />
|}<br />
<br />
===Overview of Molecular Mechanisms===<br />
Mammals possess a total of four ''Notch'' genes, with five genes for encoding the associated ligands, Delta-like and Jagged. The ''Notch'' genes each code for a single transmembrane receptor. Extracellularly, it contains epidermal growth factor (EGF)-like repeats for ligand interaction and Lin-12-Notch (LN) repeats for regulating the interactions between the extracellular and intracellular regions. Intracellularly, Notch has seven ankyrin (ANK) repeats and a transactivation domain (TAD), as well as a proline, glutamine, serine, threonine-rich (PEST) domain for degradation of Notch.<br />
<br><br><br />
====Canonical pathway====<br />
The canonical Notch pathway is unique in that it involves direct interaction between adjacent cells, as opposed to paracrine signalling, because both the Notch ligands and Notch receptors are transmembrane proteins found in the cell membrane. Furthermore, the lack of a secondary messenger or amplification process means that the Notch pathway has limited opportunities for regulation and must therefore be tightly controlled. Depending on its developmental and cellular context, activation or inhibition of the pathway can result in a variety of cellular responses, including cell death, proliferation, or differentiation.<ref name="Introduction to Notch Signalling">Yamamoto, S., Schulze, K.L. & Bellen, H.J. (2014). Introduction to Notch Signalling. ''Notch Signaling: Methods and Protocols''. Methods in Molecular Biology: 1187</ref><br />
<br><br><br />
Four Notch proteins are involved in the canonical pathway. NOTCH1 to NOTCH4 are single transmembrane receptors and can interact with a variety of ligands, including NOTCH ligands (e.g. Delta ligands) and Serrate ligands. There are three Delta ligands (Dll1, Dll3, and Dll4) and two Serrate ligands (Jagged1 and Jagged2) present in mammals.<ref name="Introduction to Notch Signalling"/> The binding between the Notch receptor and the ligand on the adjacent cell induces the release of the Notch intracellular domain (NICD) via a sequence of proteolytic reactions.<ref name="The Developing Human"/> Cell-cell interaction is therefore critical in the process of triggering Notch signalling.<br />
<br><br><br />
The interaction on the cell surface between Notch and its ligand on an adjacent cell causes the extracellular metalloprotease site (S2 site) to be exposed. The S2 site is then cleaved by transmembrane proteases belonging to the a disintegrin and metalloproteinase/tumour necrosis factor α converting enzyme (ADAM/TACE) family. The remaining Notch fragment subsequently undergoes two more intramembranous cleavages at the S3/S4 sites by the γ-secretase complex. Finally, the NICD is released and enters the nucleus to interacting with CSL (CBF1, Suppressor of Hairless, Lag-1). CSL is a DNA-binding protein that acts as a transcription factor by forming repressor or activator complexes that interact with Notch target genes.<ref name=PMID10075488/> To stop signalling, the NICD is phosphorylated by kinases and ubiquitinated by E3 ubiquitin ligases, which results in proteasome mediated degradation and subsequent termination of the signal.<ref name="Introduction to Notch Signalling"/><br />
<br><br><br />
====Non-canonical pathway====<br />
<br><br />
<br />
====Transcriptional regulation of Notch signalling====<br />
<br><br />
<br />
===Roles in Embryonic Development===<br />
<br />
The phylogenetically conserved Notch signalling pathway plays a crucial role in the development of multiple organ systems, and is a major regulator of stem cell fate. It is responsible for the regulation of the transcription of a number of signalling molecules, such as ''MyoD'', ''Mash1'' and ''GATA2'', which are genes controlling the fate of myogenic, neurogenic and haematopoietic stem cells, respectively. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> The following subsections will further elucidate the vital roles of Notch signalling during normal embryonic development. <br />
<br />
====Cardiovascular====<br />
'''Cardiomyocyte Specification and Differentiation'''<br />
<br />
Expression during the appropriate window of the timeline of embryogenesis of Notch receptors, ligands and downstream effector molecules elucidates a role for the Notch pathway in the earliest stages of cardiac development. It has been found to restrict the expression of specific cardiogenic genes in a spatiotemporal manner and regulate cardiac field specification as early as during gastrulation. <ref name=PMID19580804><pubmed>19580804</pubmed></ref> Interestingly, Notch has been found to play both suppressive and promoting roles in cardiogenesis.<br />
<br />
For example, it has been shown that Notch suppresses cardiomyocyte cell fate specification during early cardiogenesis. This has been demonstrated through studies such as that carried out by Rones and colleagues (2000), which used activation and inhibition of Notch signaling in Xenopus. <ref name=PMID10934030><pubmed>10934030</pubmed></ref><br />
<br />
On the other hand, studies such as that by Boni and colleagues (2008) have found that Notch signalling may also promote myogenesis from cardiac progenitor cells. <ref name=PMID18832173><pubmed>18832173</pubmed></ref> Cardiogenesis has also been promoted by downregulating Notch-1 activity in stem cells of embryos (Nemir et al., 2006).<ref name=PMID16690879><pubmed>16690879</pubmed></ref><br />
<br />
Despite the understanding that Notch signalling is crucial to embryonic myogenesis, the exact molecular mechanism remains elusive. Research by Buas and colleagues (2010) has explored such mechanisms by studying the Notch target, Hey1, which is known to suppress myogenic differentiation. They concluded that this inhibitory function of Hey1 is primarily mediated through binding near to myogenin and Mef2C promoters, which leads to cessation of target gene expression. <ref name=PMID19917614><pubmed>19917614</pubmed></ref><br />
<br />
'''Development of the Atrioventricular Canal'''<br />
<br />
A study by Rutenberg and colleagues (2006) and another by Kokubo and colleagues (2007) implicate a role for Notch signaling in the region between the atria and the ventricles of the heart (the atrioventricular canal, or AVC).<ref name=PMID17021042><pubmed>17021042</pubmed></ref> <ref name=PMID17259303><pubmed>17259303</pubmed></ref> They used chicken and mouse models, respectively, to show that other signalling factors, ''Bmp2'' and ''Tbx2'', are restricted to the AVC region by Notch signalling during development. <br />
<br />
Furthermore, Watanabe and colleagues (2006) showed that deletion of Notch targets increases ''Bmp2'' expression and expansion of the AVC tissue, however other, non-Notch restrictive factors involved in AVC development are likely to exist.<ref name=PMID16554359><pubmed>16554359</pubmed></ref> <br />
<br />
See the summary diagram below for a schematic representation of this molecular interaction during AVC development.<br />
<br />
'''Heart Valve Development'''<br />
<br />
In order for the heart valve to properly form in the embryo, endocardial to mesenchymal transformation (EMT) must occur. The Notch pathway, alongside Wnt and Bmp, has been found to regulate the process of EMT, defects in which can lead to congenital heart valve disease. Interestingly, Timmerman and colleagues (2004) demonstrated that this role of Notch may also promote oncogenic transformation. This team also showed that embryos exhibited abortive endocardial EMT if they were deficient in Notch signalling components in vivo and in vitro. <ref name=PMID14701881><pubmed>14701881</pubmed></ref> <br />
<br />
A more recent paper by Wang and colleagues (2013) further explored the underlying signalling processes and interrelationships of molecules that impact EMT. They found that Jagged1-Notch1 signalling in cells of the endocardium potentiates expression of Wnt4, which in turn carries out paracrine action on adjacent AVC tissue to upregulate Bmp2 expression and thus signal EMT. <ref name=PMID23560082><pubmed>23560082</pubmed></ref><br />
<br />
'''Trabeculation'''<br />
<br />
Trabeculation is the initial process of ventricular chamber development that forms a series of cardiomyocyte projections within the lumens of the ventricles of the heart (called trabeculae). Grego-Bessa and colleagues (2007) addressed the roles Notch plays in trabeculation through ''RBPJk'' (the gene product of which interacts with Notch) and ''Notch1'' gene manipulation. Mutants of these two genes showed perturbed expression and signalling of ''EphrinB2'', ''NRG1'' and ''BMP10'', alongside reduced proliferation of myocardiocytes. This research ultimately suggested that ''EphrinB2'' is a direct target of Notch in the endocardium that simultaneously requires the Notch-dependent action of BMP10 and NRG1 in order for ventricular myocardium proliferation and differentiation to occur normally. <ref name=PMID17336907><pubmed>17336907</pubmed></ref> Furthermore, the important process of trabeculation has recently been shown to be controlled by sequential Notch activation by an investigation by D’Amato and colleagues (2015). <ref name=PMID26641715><pubmed>26641715</pubmed></ref><br />
<br />
'''Development of the Outflow Tract'''<br />
<br />
TBC<br />
<br />
<br />
[[File:Summary Figure of Notch in Cardiac Development.jpeg|frame|center|alt=Summary of Notch Signalling in Cardiac Development|Summary of Notch Signalling in Cardiac Development<ref name=PMID24345875><pubmed>24345875</pubmed></ref>]]<br />
<br />
====Central Nervous System====<br />
'''Early Neural Differentiation'''<br />
<br />
Notch plays a major role in promoting neural commitment of cells. Lowell and colleagues (2011) used genetic manipulation to discover that the phenotype of stem cells is not affected by constitutively activated Notch in mouse embryonic stem cells (mESCs), however, interfering with Notch signalling -for example by pharmacological means- did impede neural fate determination. This role required Notch signalling via fibroblast growth factor (FGF) receptors. Furthermore, the conservation of the Notch signalling pathway within pluripotent stem cells is implied due to the existence of Notch ligands in stromal cells in human embryonic stem cells (hESCs) that induce neural differentiation. <ref name=PMID16594731><pubmed>16594731</pubmed></ref><br />
<br />
Das and colleagues (2010) manipulated Notch protein levels during specific stages of neural differentiation and found that if Notch signalling pathways were activated during day 3 of neural development for 6 hours, cell proliferation was dramatically enhanced. This was attributed to the induction by Notch of cyclin D1 expression. Without Notch signalling during neural development, there was reduced cyclin D1 levels. Manipulation of mESCs to express a dominant negative form of cyclin D1 resulted in abrogation of cell proliferation stimulated by Notch. Overall these results imply a temporally-specific role for Notch in CNS development, and that it requires cyclin D1 as a signalling molecule. <ref name=PMID20887720><pubmed>20887720</pubmed></ref><br />
<br><br><br />
<br />
====Other Systems====<br />
<br><br />
<br />
===Roles in Animal Development===<br />
====''Drosophila melanogaster''====<br />
Unlike the four Notch paralogs in humans, only one Notch homolog is present in ''Drosophila''.<ref name="Introduction to Notch Signalling"/><br />
<br />
Research has shown that Notch is crucial for the formation of longitudinal connections in the Drosophila CNS. Kuzina, Song, and Giniger (2011) created temperature-sensitive mutations of Notch genes that prevented the development of mature longitudinal axon tracts. They also found that the Notch phenotype appears at the earliest stages of the development of longitudinal connections in the CNS by observing early stage 13 embryos.<ref name=PMID21447553><pubmed>21447553</pubmed></ref><br />
<br><br><br />
<br />
====''Caenorhabditis elegans''====<br />
<br><br />
<br />
====''Danio rerio''====<br />
<br><br />
<br />
===Abnormalities in Notch signalling===<br />
====Alagille syndrome====<br />
Alagille syndrome (AGS) is an autosomal dominant, multisystem disorder that mainly affects the liver, heart, and kidney. Diagnostic characteristics of the disease include liver disease, cardiac disease, vertebral defects, eye conditions, and facial features, as well as renal and vascular abnormalities.<ref><pubmed>26548814</pubmed></ref> In 94% of clinically diagnosed cases, a mutation in the gene encoding the Notch ligand JAG1 has been identified as a contributing factor. In combination with this, a mutation in the NOTCH2 gene has also been implicated in the manifestation of AGS in some patients.<ref><pubmed>16773578</pubmed></ref><br />
<br />
<br />
====Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)====<br />
CADASIL is an autosomal-dominant disease of the small to medium-sized arteries, mainly in the brain, that leads to dementia and disability in mid-life. The symptoms, age of onset, and prognosis are variable. Distinguishing symptoms include subcortical ischemic events (60-80% of cases), cognitive impairment (60% of late stage disease), migraines (30-40%), mood disturbances (30%), and apathy (40%).<ref name="PMID21045164"><pubmed>21045164</pubmed></ref><ref name="PMID20301673"><pubmed>20301673</pubmed></ref> Approximately 5-10% of CADASIL patients also experience seizures. The mean age of onset is 45 years of age and the disease duration is between 10–40 years. More than 95% of CADASIL cases present with pathogenic mutations in NOTCH3 (located on chromosome 19p13), specifically the epidermal growth factor-like repeat domain.<ref name="PMID20301673"/><ref><pubmed>24579972</pubmed></ref> The NOTCH3 gene is involved in the normal development of blood vessels in both fetal and adult brains. In adults, NOTCH3 is expressed in the smooth muscle cells of arteries.<ref name="PMID21045164"/> There is currently no effective treatment available for CADASIL.<br />
<br />
====Congenital Heart Defects====<br />
<br />
<br><br><br />
<br />
===Current Areas of Research===<br />
<br><br />
<br />
<br />
===Glossary===<br />
<br />
'''Gastrulation'''<br />
<br />
Describes the formative process of the formation of the trilaminar embryo containing the three germ layers.<ref name="The Developing Human">Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2015). The developing human: clinically oriented embryology (10th ed.). Philadelphia: Saunders.</ref><br />
<br />
===References===<br />
<references/></div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z5014803&diff=248852
User:Z5014803
2016-09-23T03:47:01Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Student2016}}<br />
<br />
==Lab Attendance==<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 18:29, 5 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:40, 12 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:07, 19 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:09, 26 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:45, 2 September 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:13, 9 September 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:46, 23 September 2016 (AEST)<br />
<br />
<br />
===Belbin Team Roles===<br />
In my previous courses, I was introduced to the Bebin model team roles as a way to identify myself in a team scenario. I definitely see myself as a "Shaper" since I am driven to try and complete the task at hand as soon as possible to ensure sufficient time for the editing process and the refining of the task. I also agree that I motivate other team members to progress through the task at a efficient pace such that the group does not lose momentum. I am also a person who is not afraid to speak my mind and thus will contest other viewpoints in order to spark a discussion. I identify myself as a very dynamic person in the way that I act according to the different predicaments I'm in and this results in numerous ways of efficiently solving any problems. Although I identify myself as a Shape I do not agree that i can become aggressive or bad humoured as I see some traits of a Co-ordinator in me. I have a very mature approach and recognise that each individual has a different way of attacking a problem and have learnt to appreciate others. <br />
<br />
===Lecture 1: Fertilisation===<br />
I have always been fond of the details surrounding fertilisation as it seems like a very interesting topic. It is more than just a sperm and egg cell coming together. The first lecture on fertilisation highlighted the various processes that need to occur in order to form a zygote, from gametogenesis to fertilisation and then forming the zygote. In my first year studies I learnt that there is a mechanism to prevent multiple sperm cells to enter the ovum but wasnt familiar with the process. The most interesting aspect of this lecture was precisely the process from fertilisation to the prevention of polyspermy. I was intrigued by how sperm cells are attracted to the oocyte which was through the ZP2 protein and only the nucleus of the spermatozoa enters the cell membranes. I was also interested in how membrane fusion will result in oocyte processes that will prevent polyspermy through the elevation of intracellular calcium levels. I had minimal knowledge of this topic but the lecture really made me want to learn about this process in a lot more detail. <br />
<br />
==New SubHeading==<br />
===External Link===<br />
[http://www.smh.com.au/ SMH]<br />
<br />
===Internal Link===<br />
[[ANAT2341 Lab 1]]<br />
<br />
[[ANAT2341 Lab 1|Fertilization Lab]]<br />
<br />
[[Student Page]]<br />
<br />
==Referencing==<br />
[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=fertilization fertilization]<br />
<br />
PMID 27486480<br />
<br />
==Assessment 1==<br />
<br />
<pubmed>27486266</pubmed> <br />
<br />
In order for fertilization to occur spermatozoa must be activated in a process known as 'sperm capacitation'. The primary research article "Seminal vesicle proteins SVS3 and SVS4 facilitate SVS2 effect on sperm capacitation" by Araki et al (2016) investigate the role of seminal vesicle secretion and how they inhibit the activation of spermatozoa and how they reduce the fertility of the capacitated spermatozoa (decapacitation). In previous studies it has already been shown that SVS2 acts as a capacitation inhibitor and a decapacitation factor and Araki et al (2016) build up on this pre existent knowledge about SVSs other than SVS2. The investigation utilised CD-1 mice, in particular female mice, to show the effects of SVS3 and SVS4 on sperm cells in the female reproductive tract. <br />
<br />
<br />
Levels of SVS3 and SVS4 were measured in each part of the female reproductive tract such as the copulaatory plug, vagina, oviduct and uterine region near the vagina and oviduct 1.5 hours post copulation. By using anti SVS3 antibody there were clear indications as to the specific roles of SVS3. Results showed that there were no SVS3 proteins in any of the aforementioned parts of the reproductive tract and thus the protein alone had no effects on sperm capacitation. In saying that, SVS3 proteins did show that they had the ability to potentiate the effects of SVS2. Similarly anti SVS4 antibody was utilised to provide insight into the function of this particular protein. Contrary to the findings for SVS3, SVS4 was detected in the uterus but not in any other part of the tract. This suggests that SVS4 has similar activity to that of SVS2 in a way that both the proteins enter the uterus. Thus, SVS4 acts as a capacitation inhibitor similar to SVS2 but results indicated that it does not have the decapacitation effect like SVS2.<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 18 August 2016 - You have added the citation correctly and written a good summary of this very recent article, still only available in the pre-published submitted format, findings. One thing, you must always include the full term in your summary (even if it appears in the paper title) before you begin to use the acronym. "SVS" (seminal vesicle protein secretion) could and may mean different things in different contexts.<br />
<br />
<br />
| width=100px| Assessment 5/5<br />
|}<br />
<br />
==Assessment 2==<br />
<br />
[[File:Development_of_mouse_embryo_in_early_stages.png|400px|thumb|centre|Live imaging of the whole mouse embryo at E6 (A to D) and E5.5. (E to H)<ref><pubmed>23861733</pubmed></ref>]]<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 29 August 2016 - Reference and Copyright correctly included with the file and referenced on your page here. You have not included the <nowiki>{{Student Image}}</nowiki> template in the file summary box.<br />
<br />
| Assessment 4.5/5<br />
|}<br />
<br />
===References===<br />
<br />
<br />
<br />
== Lab 3 Assessment ==<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 31 August 2016 - Lab 3 Assessment Quiz - [[Lecture_-_Mesoderm_Development|Mesoderm]] and [[Lecture_-_Ectoderm_Development|Ectoderm]] development. All correct, Well done!<br />
<br />
| Assessment 5/5<br />
|}<br />
<br />
<br />
==Assessment 4==<br />
==Quiz==<br />
<br />
<quiz display=simple><br />
<br />
{Which of the following structures does the ectoderm contribute to?<br />
|type="()"}<br />
- epithelium, mesentry, connective tissue<br />
+ enteric nervous system<br />
- epithelium and smooth muscle<br />
- enteric nervous system, connective tissue, smooth muscle<br />
|| Option two is correct as the ectoderm only contributes to the enteric nervous system. Epithelium is contributed by the endoderm, whereas the mesentry, connective tissues, smooth muscle, blood vessels are contributed by the mesoderm<br />
<br />
{What lies rostral in relation to the notochord?<br />
|type="()"}<br />
- mesoderm<br />
- the neural tube<br />
+ the buccopharyngeal membrane<br />
- the mesoderm then endoderm<br />
|| The buccopharyngeal membrane lies rostral in relation to the notochord. The mesoderm lies laterally to the notochord, the neural tube dorsally and the mesoderm and endoderm ventrally.<br />
<br />
{During Week 8- 10 (GA 10- 12 weeks):<br />
|type="()"}<br />
+ neural crest migrates into the wall forms enteric nervous system<br />
- endoderm in the GIT wall proliferates<br />
- a second rotation (of 90 degrees) occurs on the longitudinal axis establishing the adult orientation of the stomach.<br />
- mesoderm within the dorsal mesogastrium form a long strip of cells adjacent to the forming stomach above the developing pancreas<br />
|| Option A is correct and is the only one that occurs during weeks 8-10. Option B occurs at the beginning of Week 5. Option C occurs during Week 4. Option D also occurs in Week 5 and is incorrect<br />
<br />
{Narrowing of a lumen such as the duodenum or the pylorus is also called:<br />
|type="()"}<br />
- duplication<br />
- atresia.<br />
+ stenosis<br />
- gastroschisis<br />
|| Stenosis is the correct answer. Duplication is the incomplete recanalization resulting in parallel lumens, this is really a specialized form of stenosis. Atresia is the interuption of the lumen and gastroschisis is a congenital abdominal wall defect which results in herniation of fetal abdominal viscera into the amniotic cavity.<br />
<br />
</quiz><br />
<br />
[[Student Page]]<br />
<br />
==Lab 6 Assessment==<br />
<br />
Completed ANAT2341 Lab 5 - Course Feedback Questionnaire<br />
<br />
==Lab 6 Assessment==<br />
<br />
===Identify a known genetic mutation that is associated with cleft lip or palate===<br />
<br />
Tbx22 mutations are associated with cleft lip/palate<br />
<br />
===Identify a recent research article on this gene===<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/21375406 Arunee Kaewkhampa, D.D.S., M.S., Dhirawat Jotikasthira, D.D.S., M.S., Sutti Malaivijitnond, D.D.S., M.S.,<br />
Piranit Kantaputra, D.D.S., M.S '''TBX22 Mutation Associated With Cleft Lip/Palate, Hypodontia, and Limb Anomaly''' Cleft Palate Craniofacial Journal.: 2012, 49(2); 240-4 PubMed 21375406]<br />
<br />
===How does this mutation affect developmental signalling in normal development===<br />
<br />
<br />
==Lab 7 Assessment==<br />
<br />
===Muscular Dystrophy===<br />
<br />
'''''What is/are the dystrophin mutation(s)?'''''<br />
<br />
The mutations in the dystrophin gene can sequentially lead to two types of muscular dystrophies; Duchene (DMD) and Becker (BMD) muscular dystrophy. DMD is the largest known gene in humans measuring 2.4Mb. The gene provides the coding for the a protein called dystrophin which is located primarily in muscles (skeletal and cardiac) and in minor quantities in nerve cells. In most cases mutations in this gene are of the deletion type in which pieces of DNA are lost. Other types of mutations include large duplications (pieces of DNA are copied) and point mutations (small changes in the DNA code). The aforementioned dystrophies arise from deletions in the dystrophin gene. <br />
<ref name="PMID23961084 "><pubmed>23961084</pubmed></ref><br />
<br />
<br />
'''''What is the function of dystrophin?'''''<br />
<br />
The dystrophin protein provides a structural link between the cytoskeleton of muscles and the extracellular matrix which attributes to maintaining the muscle integrity. It is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Although not much is known about the protein it is thought to cause membrane stabilisation and a lack of the protein can activate multiple pathophysiological processes. <br />
<ref name="PMID11917091"><pubmed>11917091</pubmed></ref><br />
<br />
<br />
'''''What other tissues/organs are affected by this disorder?'''''<br />
<br />
A gradual deterioration in lung function occurs as respiratory muscles weaken resulting in respiratory failure. The heart can also be affected in 1 of 2 ways namely abnormal heart rhythms and cardiomyopathy. <br />
<br />
<br />
<br />
'''''What therapies exist for DMD?'''''<br />
<br />
There is no cure for the disease as of yet but there are various research programs worldwide tackling this issue. There are also measures that can help manage the condition and improve quality of life. These include exercise, supportive environment, medical treatment (steroid treatment mostly), nutrition, surgeries, and palliative care. Other therapies that are currently under going research include gene therapy, reading through stop signals, stem cell therapy, utrophin upregulation, moosting muscle growth and reducing muscle damage<br />
<ref name="PMID22533379"><pubmed>22533379</pubmed></ref> <br />
<br />
<br />
'''''What animal models are available for muscular dystrophy?'''''<br />
<br />
The mouse is used animal model for muscular dystrophy. Other animal that have been utilised include the golden retriever dog and pigs. <br />
<ref name="PMID22137430"><pubmed>22137430</pubmed></ref></div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z5014803&diff=248642
User:Z5014803
2016-09-22T16:36:29Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Student2016}}<br />
<br />
==Lab Attendance==<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 18:29, 5 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:40, 12 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:07, 19 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:09, 26 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:45, 2 September 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:13, 9 September 2016 (AEST)<br />
<br />
<br />
===Belbin Team Roles===<br />
In my previous courses, I was introduced to the Bebin model team roles as a way to identify myself in a team scenario. I definitely see myself as a "Shaper" since I am driven to try and complete the task at hand as soon as possible to ensure sufficient time for the editing process and the refining of the task. I also agree that I motivate other team members to progress through the task at a efficient pace such that the group does not lose momentum. I am also a person who is not afraid to speak my mind and thus will contest other viewpoints in order to spark a discussion. I identify myself as a very dynamic person in the way that I act according to the different predicaments I'm in and this results in numerous ways of efficiently solving any problems. Although I identify myself as a Shape I do not agree that i can become aggressive or bad humoured as I see some traits of a Co-ordinator in me. I have a very mature approach and recognise that each individual has a different way of attacking a problem and have learnt to appreciate others. <br />
<br />
===Lecture 1: Fertilisation===<br />
I have always been fond of the details surrounding fertilisation as it seems like a very interesting topic. It is more than just a sperm and egg cell coming together. The first lecture on fertilisation highlighted the various processes that need to occur in order to form a zygote, from gametogenesis to fertilisation and then forming the zygote. In my first year studies I learnt that there is a mechanism to prevent multiple sperm cells to enter the ovum but wasnt familiar with the process. The most interesting aspect of this lecture was precisely the process from fertilisation to the prevention of polyspermy. I was intrigued by how sperm cells are attracted to the oocyte which was through the ZP2 protein and only the nucleus of the spermatozoa enters the cell membranes. I was also interested in how membrane fusion will result in oocyte processes that will prevent polyspermy through the elevation of intracellular calcium levels. I had minimal knowledge of this topic but the lecture really made me want to learn about this process in a lot more detail. <br />
<br />
==New SubHeading==<br />
===External Link===<br />
[http://www.smh.com.au/ SMH]<br />
<br />
===Internal Link===<br />
[[ANAT2341 Lab 1]]<br />
<br />
[[ANAT2341 Lab 1|Fertilization Lab]]<br />
<br />
[[Student Page]]<br />
<br />
==Referencing==<br />
[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=fertilization fertilization]<br />
<br />
PMID 27486480<br />
<br />
==Assessment 1==<br />
<br />
<pubmed>27486266</pubmed> <br />
<br />
In order for fertilization to occur spermatozoa must be activated in a process known as 'sperm capacitation'. The primary research article "Seminal vesicle proteins SVS3 and SVS4 facilitate SVS2 effect on sperm capacitation" by Araki et al (2016) investigate the role of seminal vesicle secretion and how they inhibit the activation of spermatozoa and how they reduce the fertility of the capacitated spermatozoa (decapacitation). In previous studies it has already been shown that SVS2 acts as a capacitation inhibitor and a decapacitation factor and Araki et al (2016) build up on this pre existent knowledge about SVSs other than SVS2. The investigation utilised CD-1 mice, in particular female mice, to show the effects of SVS3 and SVS4 on sperm cells in the female reproductive tract. <br />
<br />
<br />
Levels of SVS3 and SVS4 were measured in each part of the female reproductive tract such as the copulaatory plug, vagina, oviduct and uterine region near the vagina and oviduct 1.5 hours post copulation. By using anti SVS3 antibody there were clear indications as to the specific roles of SVS3. Results showed that there were no SVS3 proteins in any of the aforementioned parts of the reproductive tract and thus the protein alone had no effects on sperm capacitation. In saying that, SVS3 proteins did show that they had the ability to potentiate the effects of SVS2. Similarly anti SVS4 antibody was utilised to provide insight into the function of this particular protein. Contrary to the findings for SVS3, SVS4 was detected in the uterus but not in any other part of the tract. This suggests that SVS4 has similar activity to that of SVS2 in a way that both the proteins enter the uterus. Thus, SVS4 acts as a capacitation inhibitor similar to SVS2 but results indicated that it does not have the decapacitation effect like SVS2.<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 18 August 2016 - You have added the citation correctly and written a good summary of this very recent article, still only available in the pre-published submitted format, findings. One thing, you must always include the full term in your summary (even if it appears in the paper title) before you begin to use the acronym. "SVS" (seminal vesicle protein secretion) could and may mean different things in different contexts.<br />
<br />
<br />
| width=100px| Assessment 5/5<br />
|}<br />
<br />
==Assessment 2==<br />
<br />
[[File:Development_of_mouse_embryo_in_early_stages.png|400px|thumb|centre|Live imaging of the whole mouse embryo at E6 (A to D) and E5.5. (E to H)<ref><pubmed>23861733</pubmed></ref>]]<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 29 August 2016 - Reference and Copyright correctly included with the file and referenced on your page here. You have not included the <nowiki>{{Student Image}}</nowiki> template in the file summary box.<br />
<br />
| Assessment 4.5/5<br />
|}<br />
<br />
===References===<br />
<br />
<br />
<br />
== Lab 3 Assessment ==<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 31 August 2016 - Lab 3 Assessment Quiz - [[Lecture_-_Mesoderm_Development|Mesoderm]] and [[Lecture_-_Ectoderm_Development|Ectoderm]] development. All correct, Well done!<br />
<br />
| Assessment 5/5<br />
|}<br />
<br />
<br />
==Assessment 4==<br />
==Quiz==<br />
<br />
<quiz display=simple><br />
<br />
{Which of the following structures does the ectoderm contribute to?<br />
|type="()"}<br />
- epithelium, mesentry, connective tissue<br />
+ enteric nervous system<br />
- epithelium and smooth muscle<br />
- enteric nervous system, connective tissue, smooth muscle<br />
|| Option two is correct as the ectoderm only contributes to the enteric nervous system. Epithelium is contributed by the endoderm, whereas the mesentry, connective tissues, smooth muscle, blood vessels are contributed by the mesoderm<br />
<br />
{What lies rostral in relation to the notochord?<br />
|type="()"}<br />
- mesoderm<br />
- the neural tube<br />
+ the buccopharyngeal membrane<br />
- the mesoderm then endoderm<br />
|| The buccopharyngeal membrane lies rostral in relation to the notochord. The mesoderm lies laterally to the notochord, the neural tube dorsally and the mesoderm and endoderm ventrally.<br />
<br />
{During Week 8- 10 (GA 10- 12 weeks):<br />
|type="()"}<br />
+ neural crest migrates into the wall forms enteric nervous system<br />
- endoderm in the GIT wall proliferates<br />
- a second rotation (of 90 degrees) occurs on the longitudinal axis establishing the adult orientation of the stomach.<br />
- mesoderm within the dorsal mesogastrium form a long strip of cells adjacent to the forming stomach above the developing pancreas<br />
|| Option A is correct and is the only one that occurs during weeks 8-10. Option B occurs at the beginning of Week 5. Option C occurs during Week 4. Option D also occurs in Week 5 and is incorrect<br />
<br />
{Narrowing of a lumen such as the duodenum or the pylorus is also called:<br />
|type="()"}<br />
- duplication<br />
- atresia.<br />
+ stenosis<br />
- gastroschisis<br />
|| Stenosis is the correct answer. Duplication is the incomplete recanalization resulting in parallel lumens, this is really a specialized form of stenosis. Atresia is the interuption of the lumen and gastroschisis is a congenital abdominal wall defect which results in herniation of fetal abdominal viscera into the amniotic cavity.<br />
<br />
</quiz><br />
<br />
[[Student Page]]<br />
<br />
==Lab 6 Assessment==<br />
<br />
Completed ANAT2341 Lab 5 - Course Feedback Questionnaire<br />
<br />
==Lab 6 Assessment==<br />
<br />
===Identify a known genetic mutation that is associated with cleft lip or palate===<br />
<br />
Tbx22 mutations are associated with cleft lip/palate<br />
<br />
===Identify a recent research article on this gene===<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/21375406 Arunee Kaewkhampa, D.D.S., M.S., Dhirawat Jotikasthira, D.D.S., M.S., Sutti Malaivijitnond, D.D.S., M.S.,<br />
Piranit Kantaputra, D.D.S., M.S '''TBX22 Mutation Associated With Cleft Lip/Palate, Hypodontia, and Limb Anomaly''' Cleft Palate Craniofacial Journal.: 2012, 49(2); 240-4 PubMed 21375406]<br />
<br />
===How does this mutation affect developmental signalling in normal development===<br />
<br />
<br />
==Lab 7 Assessment==<br />
<br />
===Muscular Dystrophy===<br />
<br />
'''''What is/are the dystrophin mutation(s)?'''''<br />
<br />
The mutations in the dystrophin gene can sequentially lead to two types of muscular dystrophies; Duchene (DMD) and Becker (BMD) muscular dystrophy. DMD is the largest known gene in humans measuring 2.4Mb. The gene provides the coding for the a protein called dystrophin which is located primarily in muscles (skeletal and cardiac) and in minor quantities in nerve cells. In most cases mutations in this gene are of the deletion type in which pieces of DNA are lost. Other types of mutations include large duplications (pieces of DNA are copied) and point mutations (small changes in the DNA code). The aforementioned dystrophies arise from deletions in the dystrophin gene. <br />
<ref name="PMID23961084 "><pubmed>23961084</pubmed></ref><br />
<br />
<br />
'''''What is the function of dystrophin?'''''<br />
<br />
The dystrophin protein provides a structural link between the cytoskeleton of muscles and the extracellular matrix which attributes to maintaining the muscle integrity. It is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Although not much is known about the protein it is thought to cause membrane stabilisation and a lack of the protein can activate multiple pathophysiological processes. <br />
<ref name="PMID11917091"><pubmed>11917091</pubmed></ref><br />
<br />
<br />
'''''What other tissues/organs are affected by this disorder?'''''<br />
<br />
A gradual deterioration in lung function occurs as respiratory muscles weaken resulting in respiratory failure. The heart can also be affected in 1 of 2 ways namely abnormal heart rhythms and cardiomyopathy. <br />
<br />
<br />
<br />
'''''What therapies exist for DMD?'''''<br />
<br />
There is no cure for the disease as of yet but there are various research programs worldwide tackling this issue. There are also measures that can help manage the condition and improve quality of life. These include exercise, supportive environment, medical treatment (steroid treatment mostly), nutrition, surgeries, and palliative care. Other therapies that are currently under going research include gene therapy, reading through stop signals, stem cell therapy, utrophin upregulation, moosting muscle growth and reducing muscle damage<br />
<ref name="PMID22533379"><pubmed>22533379</pubmed></ref> <br />
<br />
<br />
'''''What animal models are available for muscular dystrophy?'''''<br />
<br />
The mouse is used animal model for muscular dystrophy. Other animal that have been utilised include the golden retriever dog and pigs. <br />
<ref name="PMID22137430"><pubmed>22137430</pubmed></ref></div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z5014803&diff=248636
User:Z5014803
2016-09-22T16:12:18Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Student2016}}<br />
<br />
==Lab Attendance==<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 18:29, 5 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:40, 12 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:07, 19 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:09, 26 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:45, 2 September 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:13, 9 September 2016 (AEST)<br />
<br />
<br />
===Belbin Team Roles===<br />
In my previous courses, I was introduced to the Bebin model team roles as a way to identify myself in a team scenario. I definitely see myself as a "Shaper" since I am driven to try and complete the task at hand as soon as possible to ensure sufficient time for the editing process and the refining of the task. I also agree that I motivate other team members to progress through the task at a efficient pace such that the group does not lose momentum. I am also a person who is not afraid to speak my mind and thus will contest other viewpoints in order to spark a discussion. I identify myself as a very dynamic person in the way that I act according to the different predicaments I'm in and this results in numerous ways of efficiently solving any problems. Although I identify myself as a Shape I do not agree that i can become aggressive or bad humoured as I see some traits of a Co-ordinator in me. I have a very mature approach and recognise that each individual has a different way of attacking a problem and have learnt to appreciate others. <br />
<br />
===Lecture 1: Fertilisation===<br />
I have always been fond of the details surrounding fertilisation as it seems like a very interesting topic. It is more than just a sperm and egg cell coming together. The first lecture on fertilisation highlighted the various processes that need to occur in order to form a zygote, from gametogenesis to fertilisation and then forming the zygote. In my first year studies I learnt that there is a mechanism to prevent multiple sperm cells to enter the ovum but wasnt familiar with the process. The most interesting aspect of this lecture was precisely the process from fertilisation to the prevention of polyspermy. I was intrigued by how sperm cells are attracted to the oocyte which was through the ZP2 protein and only the nucleus of the spermatozoa enters the cell membranes. I was also interested in how membrane fusion will result in oocyte processes that will prevent polyspermy through the elevation of intracellular calcium levels. I had minimal knowledge of this topic but the lecture really made me want to learn about this process in a lot more detail. <br />
<br />
==New SubHeading==<br />
===External Link===<br />
[http://www.smh.com.au/ SMH]<br />
<br />
===Internal Link===<br />
[[ANAT2341 Lab 1]]<br />
<br />
[[ANAT2341 Lab 1|Fertilization Lab]]<br />
<br />
[[Student Page]]<br />
<br />
==Referencing==<br />
[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=fertilization fertilization]<br />
<br />
PMID 27486480<br />
<br />
==Assessment 1==<br />
<br />
<pubmed>27486266</pubmed> <br />
<br />
In order for fertilization to occur spermatozoa must be activated in a process known as 'sperm capacitation'. The primary research article "Seminal vesicle proteins SVS3 and SVS4 facilitate SVS2 effect on sperm capacitation" by Araki et al (2016) investigate the role of seminal vesicle secretion and how they inhibit the activation of spermatozoa and how they reduce the fertility of the capacitated spermatozoa (decapacitation). In previous studies it has already been shown that SVS2 acts as a capacitation inhibitor and a decapacitation factor and Araki et al (2016) build up on this pre existent knowledge about SVSs other than SVS2. The investigation utilised CD-1 mice, in particular female mice, to show the effects of SVS3 and SVS4 on sperm cells in the female reproductive tract. <br />
<br />
<br />
Levels of SVS3 and SVS4 were measured in each part of the female reproductive tract such as the copulaatory plug, vagina, oviduct and uterine region near the vagina and oviduct 1.5 hours post copulation. By using anti SVS3 antibody there were clear indications as to the specific roles of SVS3. Results showed that there were no SVS3 proteins in any of the aforementioned parts of the reproductive tract and thus the protein alone had no effects on sperm capacitation. In saying that, SVS3 proteins did show that they had the ability to potentiate the effects of SVS2. Similarly anti SVS4 antibody was utilised to provide insight into the function of this particular protein. Contrary to the findings for SVS3, SVS4 was detected in the uterus but not in any other part of the tract. This suggests that SVS4 has similar activity to that of SVS2 in a way that both the proteins enter the uterus. Thus, SVS4 acts as a capacitation inhibitor similar to SVS2 but results indicated that it does not have the decapacitation effect like SVS2.<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 18 August 2016 - You have added the citation correctly and written a good summary of this very recent article, still only available in the pre-published submitted format, findings. One thing, you must always include the full term in your summary (even if it appears in the paper title) before you begin to use the acronym. "SVS" (seminal vesicle protein secretion) could and may mean different things in different contexts.<br />
<br />
<br />
| width=100px| Assessment 5/5<br />
|}<br />
<br />
==Assessment 2==<br />
<br />
[[File:Development_of_mouse_embryo_in_early_stages.png|400px|thumb|centre|Live imaging of the whole mouse embryo at E6 (A to D) and E5.5. (E to H)<ref><pubmed>23861733</pubmed></ref>]]<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 29 August 2016 - Reference and Copyright correctly included with the file and referenced on your page here. You have not included the <nowiki>{{Student Image}}</nowiki> template in the file summary box.<br />
<br />
| Assessment 4.5/5<br />
|}<br />
<br />
===References===<br />
<br />
<br />
<br />
== Lab 3 Assessment ==<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 31 August 2016 - Lab 3 Assessment Quiz - [[Lecture_-_Mesoderm_Development|Mesoderm]] and [[Lecture_-_Ectoderm_Development|Ectoderm]] development. All correct, Well done!<br />
<br />
| Assessment 5/5<br />
|}<br />
<br />
<br />
==Assessment 4==<br />
==Quiz==<br />
<br />
<quiz display=simple><br />
<br />
{Which of the following structures does the ectoderm contribute to?<br />
|type="()"}<br />
- epithelium, mesentry, connective tissue<br />
+ enteric nervous system<br />
- epithelium and smooth muscle<br />
- enteric nervous system, connective tissue, smooth muscle<br />
|| Option two is correct as the ectoderm only contributes to the enteric nervous system. Epithelium is contributed by the endoderm, whereas the mesentry, connective tissues, smooth muscle, blood vessels are contributed by the mesoderm<br />
<br />
{What lies rostral in relation to the notochord?<br />
|type="()"}<br />
- mesoderm<br />
- the neural tube<br />
+ the buccopharyngeal membrane<br />
- the mesoderm then endoderm<br />
|| The buccopharyngeal membrane lies rostral in relation to the notochord. The mesoderm lies laterally to the notochord, the neural tube dorsally and the mesoderm and endoderm ventrally.<br />
<br />
{During Week 8- 10 (GA 10- 12 weeks):<br />
|type="()"}<br />
+ neural crest migrates into the wall forms enteric nervous system<br />
- endoderm in the GIT wall proliferates<br />
- a second rotation (of 90 degrees) occurs on the longitudinal axis establishing the adult orientation of the stomach.<br />
- mesoderm within the dorsal mesogastrium form a long strip of cells adjacent to the forming stomach above the developing pancreas<br />
|| Option A is correct and is the only one that occurs during weeks 8-10. Option B occurs at the beginning of Week 5. Option C occurs during Week 4. Option D also occurs in Week 5 and is incorrect<br />
<br />
{Narrowing of a lumen such as the duodenum or the pylorus is also called:<br />
|type="()"}<br />
- duplication<br />
- atresia.<br />
+ stenosis<br />
- gastroschisis<br />
|| Stenosis is the correct answer. Duplication is the incomplete recanalization resulting in parallel lumens, this is really a specialized form of stenosis. Atresia is the interuption of the lumen and gastroschisis is a congenital abdominal wall defect which results in herniation of fetal abdominal viscera into the amniotic cavity.<br />
<br />
</quiz><br />
<br />
[[Student Page]]<br />
<br />
==Lab 6 Assessment==<br />
<br />
Completed ANAT2341 Lab 5 - Course Feedback Questionnaire<br />
<br />
==Lab 6 Assessment==<br />
<br />
===Identify a known genetic mutation that is associated with cleft lip or palate===<br />
<br />
Tbx22 mutations are associated with cleft lip/palate<br />
<br />
===Identify a recent research article on this gene===<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/21375406 Arunee Kaewkhampa, D.D.S., M.S., Dhirawat Jotikasthira, D.D.S., M.S., Sutti Malaivijitnond, D.D.S., M.S.,<br />
Piranit Kantaputra, D.D.S., M.S '''TBX22 Mutation Associated With Cleft Lip/Palate, Hypodontia, and Limb Anomaly''' Cleft Palate Craniofacial Journal.: 2012, 49(2); 240-4 PubMed 21375406]<br />
<br />
===How does this mutation affect developmental signalling in normal development===<br />
<br />
<br />
==Lab 7 Assessment==<br />
<br />
===Muscular Dystrophy===<br />
<br />
'''''What is/are the dystrophin mutation(s)?'''''<br />
<br />
The mutations in the dystrophin gene can sequentially lead to two types of muscular dystrophies; Duchene (DMD) and Becker (BMD) muscular dystrophy. DMD is the largest known gene in humans measuring 2.4Mb. The gene provides the coding for the a protein called dystrophin which is located primarily in muscles (skeletal and cardiac) and in minor quantities in nerve cells. In most cases mutations in this gene are of the deletion type in which pieces of DNA are lost. Other types of mutations include large duplications (pieces of DNA are copied) and point mutations (small changes in the DNA code). The aforementioned dystrophies arise from deletions in the dystrophin gene. <br />
<ref name="PMID23961084 "><pubmed>23961084</pubmed></ref><br />
<br />
<br />
'''''What is the function of dystrophin?'''''<br />
<br />
The dystrophin protein is a component of the large protein complex: the dystrophin-glycoprotein complex (DGC). The DGC spans the sarcolemma (the cell membrane of skeletal muscle fibre cells) binds to surrounding ligands and to dystrophin inside the cell. <br />
<ref name="PMID25086336"><pubmed>25086336</pubmed></ref><br />
This complex is responsible for stabilising the sarcolemma by integrating the components of the cytoskeleton of muscle cells. These interactions of the dystrophin protein with components such as the actin filaments and microtubules of the muscle cell are mediated by dystrophin’s four main functional domains. It has also been found that dystrophin may bind membrane phospholipids to further support its stabilisation of the sarcolemma. <ref name="PMID26140716"><pubmed>26140716</pubmed></ref><br />
<br />
'''''What other tissues/organs are affected by this disorder?'''''<br />
<br />
The heart has been found to be affected by some forms muscular dystrophy, including cardiac complications such as heart failure and/or arrhythmias. <ref name="PMID27340611"><pubmed>27340611</pubmed></ref> Moreover, respiratory failure due to the breathing muscles becoming weak severely limits the lifespan of DMD patients. <ref name="PMID26140716"><pubmed>26140716</pubmed></ref><br />
<br />
'''''What therapies exist for DMD?'''''<br />
<br />
Extensive research surrounds the use of gene replacement therapy for all mutation-types of DMD. However, the extremely long nature of the dystrophin gene renders it difficult to replace and many other challenges remain such as with the nature of the viral vectors used in gene replacement. A number of other genetics-based approaches are being investigated such as gene product modifiers (exon-skipping) and utrophin modulation strategies. <ref name="PMID26140505"><pubmed>26140505</pubmed></ref> <ref name="PMID26140716"><pubmed>26140716</pubmed></ref><br />
Pharmacological treatment for DMD involves administration of corticosteroids for suppression of the associated inflammation in the muscles, however this has significant side effects and questionable therapeutic efficacy.<br />
<ref name="PMID27621596"><pubmed>27621596</pubmed></ref><br />
<br />
<br />
'''''What animal models are available for muscular dystrophy?'''''<br />
<br />
The mouse is probably the most widely used animal model for muscular dystrophy. Other animal models that have been utilised include the golden retriever dog and pigs. <ref name="PMID26140716"><pubmed>26140716</pubmed></ref> <ref name="PMID22968479"><pubmed>22968479</pubmed></ref> <ref name="PMID27634466"><pubmed>27634466</pubmed></ref></div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z5014803&diff=247604
User:Z5014803
2016-09-15T13:03:54Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Student2016}}<br />
<br />
==Lab Attendance==<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 18:29, 5 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:40, 12 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:07, 19 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:09, 26 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:45, 2 September 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:13, 9 September 2016 (AEST)<br />
<br />
<br />
===Belbin Team Roles===<br />
In my previous courses, I was introduced to the Bebin model team roles as a way to identify myself in a team scenario. I definitely see myself as a "Shaper" since I am driven to try and complete the task at hand as soon as possible to ensure sufficient time for the editing process and the refining of the task. I also agree that I motivate other team members to progress through the task at a efficient pace such that the group does not lose momentum. I am also a person who is not afraid to speak my mind and thus will contest other viewpoints in order to spark a discussion. I identify myself as a very dynamic person in the way that I act according to the different predicaments I'm in and this results in numerous ways of efficiently solving any problems. Although I identify myself as a Shape I do not agree that i can become aggressive or bad humoured as I see some traits of a Co-ordinator in me. I have a very mature approach and recognise that each individual has a different way of attacking a problem and have learnt to appreciate others. <br />
<br />
===Lecture 1: Fertilisation===<br />
I have always been fond of the details surrounding fertilisation as it seems like a very interesting topic. It is more than just a sperm and egg cell coming together. The first lecture on fertilisation highlighted the various processes that need to occur in order to form a zygote, from gametogenesis to fertilisation and then forming the zygote. In my first year studies I learnt that there is a mechanism to prevent multiple sperm cells to enter the ovum but wasnt familiar with the process. The most interesting aspect of this lecture was precisely the process from fertilisation to the prevention of polyspermy. I was intrigued by how sperm cells are attracted to the oocyte which was through the ZP2 protein and only the nucleus of the spermatozoa enters the cell membranes. I was also interested in how membrane fusion will result in oocyte processes that will prevent polyspermy through the elevation of intracellular calcium levels. I had minimal knowledge of this topic but the lecture really made me want to learn about this process in a lot more detail. <br />
<br />
==New SubHeading==<br />
===External Link===<br />
[http://www.smh.com.au/ SMH]<br />
<br />
===Internal Link===<br />
[[ANAT2341 Lab 1]]<br />
<br />
[[ANAT2341 Lab 1|Fertilization Lab]]<br />
<br />
[[Student Page]]<br />
<br />
==Referencing==<br />
[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=fertilization fertilization]<br />
<br />
PMID 27486480<br />
<br />
==Assessment 1==<br />
<br />
<pubmed>27486266</pubmed> <br />
<br />
In order for fertilization to occur spermatozoa must be activated in a process known as 'sperm capacitation'. The primary research article "Seminal vesicle proteins SVS3 and SVS4 facilitate SVS2 effect on sperm capacitation" by Araki et al (2016) investigate the role of seminal vesicle secretion and how they inhibit the activation of spermatozoa and how they reduce the fertility of the capacitated spermatozoa (decapacitation). In previous studies it has already been shown that SVS2 acts as a capacitation inhibitor and a decapacitation factor and Araki et al (2016) build up on this pre existent knowledge about SVSs other than SVS2. The investigation utilised CD-1 mice, in particular female mice, to show the effects of SVS3 and SVS4 on sperm cells in the female reproductive tract. <br />
<br />
<br />
Levels of SVS3 and SVS4 were measured in each part of the female reproductive tract such as the copulaatory plug, vagina, oviduct and uterine region near the vagina and oviduct 1.5 hours post copulation. By using anti SVS3 antibody there were clear indications as to the specific roles of SVS3. Results showed that there were no SVS3 proteins in any of the aforementioned parts of the reproductive tract and thus the protein alone had no effects on sperm capacitation. In saying that, SVS3 proteins did show that they had the ability to potentiate the effects of SVS2. Similarly anti SVS4 antibody was utilised to provide insight into the function of this particular protein. Contrary to the findings for SVS3, SVS4 was detected in the uterus but not in any other part of the tract. This suggests that SVS4 has similar activity to that of SVS2 in a way that both the proteins enter the uterus. Thus, SVS4 acts as a capacitation inhibitor similar to SVS2 but results indicated that it does not have the decapacitation effect like SVS2.<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 18 August 2016 - You have added the citation correctly and written a good summary of this very recent article, still only available in the pre-published submitted format, findings. One thing, you must always include the full term in your summary (even if it appears in the paper title) before you begin to use the acronym. "SVS" (seminal vesicle protein secretion) could and may mean different things in different contexts.<br />
<br />
<br />
| width=100px| Assessment 5/5<br />
|}<br />
<br />
==Assessment 2==<br />
<br />
[[File:Development_of_mouse_embryo_in_early_stages.png|400px|thumb|centre|Live imaging of the whole mouse embryo at E6 (A to D) and E5.5. (E to H)<ref><pubmed>23861733</pubmed></ref>]]<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 29 August 2016 - Reference and Copyright correctly included with the file and referenced on your page here. You have not included the <nowiki>{{Student Image}}</nowiki> template in the file summary box.<br />
<br />
| Assessment 4.5/5<br />
|}<br />
<br />
===References===<br />
<br />
<br />
<br />
== Lab 3 Assessment ==<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 31 August 2016 - Lab 3 Assessment Quiz - [[Lecture_-_Mesoderm_Development|Mesoderm]] and [[Lecture_-_Ectoderm_Development|Ectoderm]] development. All correct, Well done!<br />
<br />
| Assessment 5/5<br />
|}<br />
<br />
<br />
==Assessment 4==<br />
==Quiz==<br />
<br />
<quiz display=simple><br />
<br />
{Which of the following structures does the ectoderm contribute to?<br />
|type="()"}<br />
- epithelium, mesentry, connective tissue<br />
+ enteric nervous system<br />
- epithelium and smooth muscle<br />
- enteric nervous system, connective tissue, smooth muscle<br />
|| Option two is correct as the ectoderm only contributes to the enteric nervous system. Epithelium is contributed by the endoderm, whereas the mesentry, connective tissues, smooth muscle, blood vessels are contributed by the mesoderm<br />
<br />
{What lies rostral in relation to the notochord?<br />
|type="()"}<br />
- mesoderm<br />
- the neural tube<br />
+ the buccopharyngeal membrane<br />
- the mesoderm then endoderm<br />
|| The buccopharyngeal membrane lies rostral in relation to the notochord. The mesoderm lies laterally to the notochord, the neural tube dorsally and the mesoderm and endoderm ventrally.<br />
<br />
{During Week 8- 10 (GA 10- 12 weeks):<br />
|type="()"}<br />
+ neural crest migrates into the wall forms enteric nervous system<br />
- endoderm in the GIT wall proliferates<br />
- a second rotation (of 90 degrees) occurs on the longitudinal axis establishing the adult orientation of the stomach.<br />
- mesoderm within the dorsal mesogastrium form a long strip of cells adjacent to the forming stomach above the developing pancreas<br />
|| Option A is correct and is the only one that occurs during weeks 8-10. Option B occurs at the beginning of Week 5. Option C occurs during Week 4. Option D also occurs in Week 5 and is incorrect<br />
<br />
{Narrowing of a lumen such as the duodenum or the pylorus is also called:<br />
|type="()"}<br />
- duplication<br />
- atresia.<br />
+ stenosis<br />
- gastroschisis<br />
|| Stenosis is the correct answer. Duplication is the incomplete recanalization resulting in parallel lumens, this is really a specialized form of stenosis. Atresia is the interuption of the lumen and gastroschisis is a congenital abdominal wall defect which results in herniation of fetal abdominal viscera into the amniotic cavity.<br />
<br />
</quiz><br />
<br />
[[Student Page]]<br />
<br />
==Lab 6 Assessment==<br />
<br />
Completed ANAT2341 Lab 5 - Course Feedback Questionnaire<br />
<br />
==Lab 7 Assessment==<br />
<br />
===Identify a known genetic mutation that is associated with cleft lip or palate===<br />
<br />
Tbx22 mutations are associated with cleft lip/palate<br />
<br />
===Identify a recent research article on this gene===<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/21375406 Arunee Kaewkhampa, D.D.S., M.S., Dhirawat Jotikasthira, D.D.S., M.S., Sutti Malaivijitnond, D.D.S., M.S.,<br />
Piranit Kantaputra, D.D.S., M.S '''TBX22 Mutation Associated With Cleft Lip/Palate, Hypodontia, and Limb Anomaly''' Cleft Palate Craniofacial Journal.: 2012, 49(2); 240-4 PubMed 21375406]<br />
<br />
===How does this mutation affect developmental signalling in normal development===</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z5014803&diff=247578
User:Z5014803
2016-09-15T12:44:37Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Student2016}}<br />
<br />
==Lab Attendance==<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 18:29, 5 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:40, 12 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:07, 19 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:09, 26 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:45, 2 September 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:13, 9 September 2016 (AEST)<br />
<br />
<br />
===Belbin Team Roles===<br />
In my previous courses, I was introduced to the Bebin model team roles as a way to identify myself in a team scenario. I definitely see myself as a "Shaper" since I am driven to try and complete the task at hand as soon as possible to ensure sufficient time for the editing process and the refining of the task. I also agree that I motivate other team members to progress through the task at a efficient pace such that the group does not lose momentum. I am also a person who is not afraid to speak my mind and thus will contest other viewpoints in order to spark a discussion. I identify myself as a very dynamic person in the way that I act according to the different predicaments I'm in and this results in numerous ways of efficiently solving any problems. Although I identify myself as a Shape I do not agree that i can become aggressive or bad humoured as I see some traits of a Co-ordinator in me. I have a very mature approach and recognise that each individual has a different way of attacking a problem and have learnt to appreciate others. <br />
<br />
===Lecture 1: Fertilisation===<br />
I have always been fond of the details surrounding fertilisation as it seems like a very interesting topic. It is more than just a sperm and egg cell coming together. The first lecture on fertilisation highlighted the various processes that need to occur in order to form a zygote, from gametogenesis to fertilisation and then forming the zygote. In my first year studies I learnt that there is a mechanism to prevent multiple sperm cells to enter the ovum but wasnt familiar with the process. The most interesting aspect of this lecture was precisely the process from fertilisation to the prevention of polyspermy. I was intrigued by how sperm cells are attracted to the oocyte which was through the ZP2 protein and only the nucleus of the spermatozoa enters the cell membranes. I was also interested in how membrane fusion will result in oocyte processes that will prevent polyspermy through the elevation of intracellular calcium levels. I had minimal knowledge of this topic but the lecture really made me want to learn about this process in a lot more detail. <br />
<br />
==New SubHeading==<br />
===External Link===<br />
[http://www.smh.com.au/ SMH]<br />
<br />
===Internal Link===<br />
[[ANAT2341 Lab 1]]<br />
<br />
[[ANAT2341 Lab 1|Fertilization Lab]]<br />
<br />
[[Student Page]]<br />
<br />
==Referencing==<br />
[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=fertilization fertilization]<br />
<br />
PMID 27486480<br />
<br />
==Assessment 1==<br />
<br />
<pubmed>27486266</pubmed> <br />
<br />
In order for fertilization to occur spermatozoa must be activated in a process known as 'sperm capacitation'. The primary research article "Seminal vesicle proteins SVS3 and SVS4 facilitate SVS2 effect on sperm capacitation" by Araki et al (2016) investigate the role of seminal vesicle secretion and how they inhibit the activation of spermatozoa and how they reduce the fertility of the capacitated spermatozoa (decapacitation). In previous studies it has already been shown that SVS2 acts as a capacitation inhibitor and a decapacitation factor and Araki et al (2016) build up on this pre existent knowledge about SVSs other than SVS2. The investigation utilised CD-1 mice, in particular female mice, to show the effects of SVS3 and SVS4 on sperm cells in the female reproductive tract. <br />
<br />
<br />
Levels of SVS3 and SVS4 were measured in each part of the female reproductive tract such as the copulaatory plug, vagina, oviduct and uterine region near the vagina and oviduct 1.5 hours post copulation. By using anti SVS3 antibody there were clear indications as to the specific roles of SVS3. Results showed that there were no SVS3 proteins in any of the aforementioned parts of the reproductive tract and thus the protein alone had no effects on sperm capacitation. In saying that, SVS3 proteins did show that they had the ability to potentiate the effects of SVS2. Similarly anti SVS4 antibody was utilised to provide insight into the function of this particular protein. Contrary to the findings for SVS3, SVS4 was detected in the uterus but not in any other part of the tract. This suggests that SVS4 has similar activity to that of SVS2 in a way that both the proteins enter the uterus. Thus, SVS4 acts as a capacitation inhibitor similar to SVS2 but results indicated that it does not have the decapacitation effect like SVS2.<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 18 August 2016 - You have added the citation correctly and written a good summary of this very recent article, still only available in the pre-published submitted format, findings. One thing, you must always include the full term in your summary (even if it appears in the paper title) before you begin to use the acronym. "SVS" (seminal vesicle protein secretion) could and may mean different things in different contexts.<br />
<br />
<br />
| width=100px| Assessment 5/5<br />
|}<br />
<br />
==Assessment 2==<br />
<br />
[[File:Development_of_mouse_embryo_in_early_stages.png|400px|thumb|centre|Live imaging of the whole mouse embryo at E6 (A to D) and E5.5. (E to H)<ref><pubmed>23861733</pubmed></ref>]]<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 29 August 2016 - Reference and Copyright correctly included with the file and referenced on your page here. You have not included the <nowiki>{{Student Image}}</nowiki> template in the file summary box.<br />
<br />
| Assessment 4.5/5<br />
|}<br />
<br />
===References===<br />
<br />
<br />
<br />
== Lab 3 Assessment ==<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 31 August 2016 - Lab 3 Assessment Quiz - [[Lecture_-_Mesoderm_Development|Mesoderm]] and [[Lecture_-_Ectoderm_Development|Ectoderm]] development. All correct, Well done!<br />
<br />
| Assessment 5/5<br />
|}<br />
<br />
<br />
==Assessment 4==<br />
==Quiz==<br />
<br />
<quiz display=simple><br />
<br />
{Which of the following structures does the ectoderm contribute to?<br />
|type="()"}<br />
- epithelium, mesentry, connective tissue<br />
+ enteric nervous system<br />
- epithelium and smooth muscle<br />
- enteric nervous system, connective tissue, smooth muscle<br />
|| Option two is correct as the ectoderm only contributes to the enteric nervous system. Epithelium is contributed by the endoderm, whereas the mesentry, connective tissues, smooth muscle, blood vessels are contributed by the mesoderm<br />
<br />
{What lies rostral in relation to the notochord?<br />
|type="()"}<br />
- mesoderm<br />
- the neural tube<br />
+ the buccopharyngeal membrane<br />
- the mesoderm then endoderm<br />
|| The buccopharyngeal membrane lies rostral in relation to the notochord. The mesoderm lies laterally to the notochord, the neural tube dorsally and the mesoderm and endoderm ventrally.<br />
<br />
{During Week 8- 10 (GA 10- 12 weeks):<br />
|type="()"}<br />
+ neural crest migrates into the wall forms enteric nervous system<br />
- endoderm in the GIT wall proliferates<br />
- a second rotation (of 90 degrees) occurs on the longitudinal axis establishing the adult orientation of the stomach.<br />
- mesoderm within the dorsal mesogastrium form a long strip of cells adjacent to the forming stomach above the developing pancreas<br />
|| Option A is correct and is the only one that occurs during weeks 8-10. Option B occurs at the beginning of Week 5. Option C occurs during Week 4. Option D also occurs in Week 5 and is incorrect<br />
<br />
{Narrowing of a lumen such as the duodenum or the pylorus is also called:<br />
|type="()"}<br />
- duplication<br />
- atresia.<br />
+ stenosis<br />
- gastroschisis<br />
|| Stenosis is the correct answer. Duplication is the incomplete recanalization resulting in parallel lumens, this is really a specialized form of stenosis. Atresia is the interuption of the lumen and gastroschisis is a congenital abdominal wall defect which results in herniation of fetal abdominal viscera into the amniotic cavity.<br />
<br />
</quiz><br />
<br />
[[Student Page]]<br />
<br />
==Lab 6 Assessment==<br />
<br />
Completed ANAT2341 Lab 5 - Course Feedback Questionnaire<br />
<br />
==Lab 7 Assessment==<br />
<br />
===Identify a known genetic mutation that is associated with cleft lip or palate===<br />
<br />
<br />
<br />
===Identify a recent research article on this gene===<br />
<br />
<br />
===How does this mutation affect developmental signalling in normal development===</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z5014803&diff=246732
User:Z5014803
2016-09-09T04:53:14Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Student2016}}<br />
<br />
==Lab Attendance==<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 18:29, 5 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:40, 12 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:07, 19 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:09, 26 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:45, 2 September 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:13, 9 September 2016 (AEST)<br />
<br />
<br />
===Belbin Team Roles===<br />
In my previous courses, I was introduced to the Bebin model team roles as a way to identify myself in a team scenario. I definitely see myself as a "Shaper" since I am driven to try and complete the task at hand as soon as possible to ensure sufficient time for the editing process and the refining of the task. I also agree that I motivate other team members to progress through the task at a efficient pace such that the group does not lose momentum. I am also a person who is not afraid to speak my mind and thus will contest other viewpoints in order to spark a discussion. I identify myself as a very dynamic person in the way that I act according to the different predicaments I'm in and this results in numerous ways of efficiently solving any problems. Although I identify myself as a Shape I do not agree that i can become aggressive or bad humoured as I see some traits of a Co-ordinator in me. I have a very mature approach and recognise that each individual has a different way of attacking a problem and have learnt to appreciate others. <br />
<br />
===Lecture 1: Fertilisation===<br />
I have always been fond of the details surrounding fertilisation as it seems like a very interesting topic. It is more than just a sperm and egg cell coming together. The first lecture on fertilisation highlighted the various processes that need to occur in order to form a zygote, from gametogenesis to fertilisation and then forming the zygote. In my first year studies I learnt that there is a mechanism to prevent multiple sperm cells to enter the ovum but wasnt familiar with the process. The most interesting aspect of this lecture was precisely the process from fertilisation to the prevention of polyspermy. I was intrigued by how sperm cells are attracted to the oocyte which was through the ZP2 protein and only the nucleus of the spermatozoa enters the cell membranes. I was also interested in how membrane fusion will result in oocyte processes that will prevent polyspermy through the elevation of intracellular calcium levels. I had minimal knowledge of this topic but the lecture really made me want to learn about this process in a lot more detail. <br />
<br />
==New SubHeading==<br />
===External Link===<br />
[http://www.smh.com.au/ SMH]<br />
<br />
===Internal Link===<br />
[[ANAT2341 Lab 1]]<br />
<br />
[[ANAT2341 Lab 1|Fertilization Lab]]<br />
<br />
[[Student Page]]<br />
<br />
==Referencing==<br />
[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=fertilization fertilization]<br />
<br />
PMID 27486480<br />
<br />
==Assessment 1==<br />
<br />
<pubmed>27486266</pubmed> <br />
<br />
In order for fertilization to occur spermatozoa must be activated in a process known as 'sperm capacitation'. The primary research article "Seminal vesicle proteins SVS3 and SVS4 facilitate SVS2 effect on sperm capacitation" by Araki et al (2016) investigate the role of seminal vesicle secretion and how they inhibit the activation of spermatozoa and how they reduce the fertility of the capacitated spermatozoa (decapacitation). In previous studies it has already been shown that SVS2 acts as a capacitation inhibitor and a decapacitation factor and Araki et al (2016) build up on this pre existent knowledge about SVSs other than SVS2. The investigation utilised CD-1 mice, in particular female mice, to show the effects of SVS3 and SVS4 on sperm cells in the female reproductive tract. <br />
<br />
<br />
Levels of SVS3 and SVS4 were measured in each part of the female reproductive tract such as the copulaatory plug, vagina, oviduct and uterine region near the vagina and oviduct 1.5 hours post copulation. By using anti SVS3 antibody there were clear indications as to the specific roles of SVS3. Results showed that there were no SVS3 proteins in any of the aforementioned parts of the reproductive tract and thus the protein alone had no effects on sperm capacitation. In saying that, SVS3 proteins did show that they had the ability to potentiate the effects of SVS2. Similarly anti SVS4 antibody was utilised to provide insight into the function of this particular protein. Contrary to the findings for SVS3, SVS4 was detected in the uterus but not in any other part of the tract. This suggests that SVS4 has similar activity to that of SVS2 in a way that both the proteins enter the uterus. Thus, SVS4 acts as a capacitation inhibitor similar to SVS2 but results indicated that it does not have the decapacitation effect like SVS2.<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 18 August 2016 - You have added the citation correctly and written a good summary of this very recent article, still only available in the pre-published submitted format, findings. One thing, you must always include the full term in your summary (even if it appears in the paper title) before you begin to use the acronym. "SVS" (seminal vesicle protein secretion) could and may mean different things in different contexts.<br />
<br />
<br />
| width=100px| Assessment 5/5<br />
|}<br />
<br />
==Assessment 2==<br />
<br />
[[File:Development_of_mouse_embryo_in_early_stages.png|400px|thumb|centre|Live imaging of the whole mouse embryo at E6 (A to D) and E5.5. (E to H)<ref><pubmed>23861733</pubmed></ref>]]<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 29 August 2016 - Reference and Copyright correctly included with the file and referenced on your page here. You have not included the <nowiki>{{Student Image}}</nowiki> template in the file summary box.<br />
<br />
| Assessment 4.5/5<br />
|}<br />
<br />
===References===<br />
<br />
<br />
<br />
== Lab 3 Assessment ==<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 31 August 2016 - Lab 3 Assessment Quiz - [[Lecture_-_Mesoderm_Development|Mesoderm]] and [[Lecture_-_Ectoderm_Development|Ectoderm]] development. All correct, Well done!<br />
<br />
| Assessment 5/5<br />
|}<br />
<br />
<br />
==Assessment 4==<br />
==Quiz==<br />
<br />
<quiz display=simple><br />
<br />
{Which of the following structures does the ectoderm contribute to?<br />
|type="()"}<br />
- epithelium, mesentry, connective tissue<br />
+ enteric nervous system<br />
- epithelium and smooth muscle<br />
- enteric nervous system, connective tissue, smooth muscle<br />
|| Option two is correct as the ectoderm only contributes to the enteric nervous system. Epithelium is contributed by the endoderm, whereas the mesentry, connective tissues, smooth muscle, blood vessels are contributed by the mesoderm<br />
<br />
{What lies rostral in relation to the notochord?<br />
|type="()"}<br />
- mesoderm<br />
- the neural tube<br />
+ the buccopharyngeal membrane<br />
- the mesoderm then endoderm<br />
|| The buccopharyngeal membrane lies rostral in relation to the notochord. The mesoderm lies laterally to the notochord, the neural tube dorsally and the mesoderm and endoderm ventrally.<br />
<br />
{During Week 8- 10 (GA 10- 12 weeks):<br />
|type="()"}<br />
+ neural crest migrates into the wall forms enteric nervous system<br />
- endoderm in the GIT wall proliferates<br />
- a second rotation (of 90 degrees) occurs on the longitudinal axis establishing the adult orientation of the stomach.<br />
- mesoderm within the dorsal mesogastrium form a long strip of cells adjacent to the forming stomach above the developing pancreas<br />
|| Option A is correct and is the only one that occurs during weeks 8-10. Option B occurs at the beginning of Week 5. Option C occurs during Week 4. Option D also occurs in Week 5 and is incorrect<br />
<br />
{Narrowing of a lumen such as the duodenum or the pylorus is also called:<br />
|type="()"}<br />
- duplication<br />
- atresia.<br />
+ stenosis<br />
- gastroschisis<br />
|| Stenosis is the correct answer. Duplication is the incomplete recanalization resulting in parallel lumens, this is really a specialized form of stenosis. Atresia is the interuption of the lumen and gastroschisis is a congenital abdominal wall defect which results in herniation of fetal abdominal viscera into the amniotic cavity.<br />
<br />
</quiz><br />
<br />
[[Student Page]]<br />
<br />
==Lab 6 Assessment==<br />
<br />
Completed ANAT2341 Lab 5 - Course Feedback Questionnaire</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z5014803&diff=246728
User:Z5014803
2016-09-09T04:50:25Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Student2016}}<br />
<br />
==Lab Attendance==<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 18:29, 5 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:40, 12 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:07, 19 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:09, 26 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:45, 2 September 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:13, 9 September 2016 (AEST)<br />
<br />
<br />
===Belbin Team Roles===<br />
In my previous courses, I was introduced to the Bebin model team roles as a way to identify myself in a team scenario. I definitely see myself as a "Shaper" since I am driven to try and complete the task at hand as soon as possible to ensure sufficient time for the editing process and the refining of the task. I also agree that I motivate other team members to progress through the task at a efficient pace such that the group does not lose momentum. I am also a person who is not afraid to speak my mind and thus will contest other viewpoints in order to spark a discussion. I identify myself as a very dynamic person in the way that I act according to the different predicaments I'm in and this results in numerous ways of efficiently solving any problems. Although I identify myself as a Shape I do not agree that i can become aggressive or bad humoured as I see some traits of a Co-ordinator in me. I have a very mature approach and recognise that each individual has a different way of attacking a problem and have learnt to appreciate others. <br />
<br />
===Lecture 1: Fertilisation===<br />
I have always been fond of the details surrounding fertilisation as it seems like a very interesting topic. It is more than just a sperm and egg cell coming together. The first lecture on fertilisation highlighted the various processes that need to occur in order to form a zygote, from gametogenesis to fertilisation and then forming the zygote. In my first year studies I learnt that there is a mechanism to prevent multiple sperm cells to enter the ovum but wasnt familiar with the process. The most interesting aspect of this lecture was precisely the process from fertilisation to the prevention of polyspermy. I was intrigued by how sperm cells are attracted to the oocyte which was through the ZP2 protein and only the nucleus of the spermatozoa enters the cell membranes. I was also interested in how membrane fusion will result in oocyte processes that will prevent polyspermy through the elevation of intracellular calcium levels. I had minimal knowledge of this topic but the lecture really made me want to learn about this process in a lot more detail. <br />
<br />
==New SubHeading==<br />
===External Link===<br />
[http://www.smh.com.au/ SMH]<br />
<br />
===Internal Link===<br />
[[ANAT2341 Lab 1]]<br />
<br />
[[ANAT2341 Lab 1|Fertilization Lab]]<br />
<br />
[[Student Page]]<br />
<br />
==Referencing==<br />
[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=fertilization fertilization]<br />
<br />
PMID 27486480<br />
<br />
==Assessment 1==<br />
<br />
<pubmed>27486266</pubmed> <br />
<br />
In order for fertilization to occur spermatozoa must be activated in a process known as 'sperm capacitation'. The primary research article "Seminal vesicle proteins SVS3 and SVS4 facilitate SVS2 effect on sperm capacitation" by Araki et al (2016) investigate the role of seminal vesicle secretion and how they inhibit the activation of spermatozoa and how they reduce the fertility of the capacitated spermatozoa (decapacitation). In previous studies it has already been shown that SVS2 acts as a capacitation inhibitor and a decapacitation factor and Araki et al (2016) build up on this pre existent knowledge about SVSs other than SVS2. The investigation utilised CD-1 mice, in particular female mice, to show the effects of SVS3 and SVS4 on sperm cells in the female reproductive tract. <br />
<br />
<br />
Levels of SVS3 and SVS4 were measured in each part of the female reproductive tract such as the copulaatory plug, vagina, oviduct and uterine region near the vagina and oviduct 1.5 hours post copulation. By using anti SVS3 antibody there were clear indications as to the specific roles of SVS3. Results showed that there were no SVS3 proteins in any of the aforementioned parts of the reproductive tract and thus the protein alone had no effects on sperm capacitation. In saying that, SVS3 proteins did show that they had the ability to potentiate the effects of SVS2. Similarly anti SVS4 antibody was utilised to provide insight into the function of this particular protein. Contrary to the findings for SVS3, SVS4 was detected in the uterus but not in any other part of the tract. This suggests that SVS4 has similar activity to that of SVS2 in a way that both the proteins enter the uterus. Thus, SVS4 acts as a capacitation inhibitor similar to SVS2 but results indicated that it does not have the decapacitation effect like SVS2.<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 18 August 2016 - You have added the citation correctly and written a good summary of this very recent article, still only available in the pre-published submitted format, findings. One thing, you must always include the full term in your summary (even if it appears in the paper title) before you begin to use the acronym. "SVS" (seminal vesicle protein secretion) could and may mean different things in different contexts.<br />
<br />
<br />
| width=100px| Assessment 5/5<br />
|}<br />
<br />
==Assessment 2==<br />
<br />
[[File:Development_of_mouse_embryo_in_early_stages.png|400px|thumb|centre|Live imaging of the whole mouse embryo at E6 (A to D) and E5.5. (E to H)<ref><pubmed>23861733</pubmed></ref>]]<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 29 August 2016 - Reference and Copyright correctly included with the file and referenced on your page here. You have not included the <nowiki>{{Student Image}}</nowiki> template in the file summary box.<br />
<br />
| Assessment 4.5/5<br />
|}<br />
<br />
===References===<br />
<br />
<br />
<br />
== Lab 3 Assessment ==<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 31 August 2016 - Lab 3 Assessment Quiz - [[Lecture_-_Mesoderm_Development|Mesoderm]] and [[Lecture_-_Ectoderm_Development|Ectoderm]] development. All correct, Well done!<br />
<br />
| Assessment 5/5<br />
|}<br />
<br />
<br />
==Assessment 4==<br />
==Quiz==<br />
<br />
<quiz display=simple><br />
<br />
{Which of the following structures does the ectoderm contribute to?<br />
|type="()"}<br />
- epithelium, mesentry, connective tissue<br />
+ enteric nervous system<br />
- epithelium and smooth muscle<br />
- enteric nervous system, connective tissue, smooth muscle<br />
|| Option two is correct as the ectoderm only contributes to the enteric nervous system. Epithelium is contributed by the endoderm, whereas the mesentry, connective tissues, smooth muscle, blood vessels are contributed by the mesoderm<br />
<br />
{What lies rostral in relation to the notochord?<br />
|type="()"}<br />
- mesoderm<br />
- the neural tube<br />
+ the buccopharyngeal membrane<br />
- the mesoderm then endoderm<br />
|| The buccopharyngeal membrane lies rostral in relation to the notochord. The mesoderm lies laterally to the notochord, the neural tube dorsally and the mesoderm and endoderm ventrally.<br />
<br />
{During Week 8- 10 (GA 10- 12 weeks):<br />
|type="()"}<br />
+ neural crest migrates into the wall forms enteric nervous system<br />
- endoderm in the GIT wall proliferates<br />
- a second rotation (of 90 degrees) occurs on the longitudinal axis establishing the adult orientation of the stomach.<br />
- mesoderm within the dorsal mesogastrium form a long strip of cells adjacent to the forming stomach above the developing pancreas<br />
|| Option A is correct and is the only one that occurs during weeks 8-10. Option B occurs at the beginning of Week 5. Option C occurs during Week 4. Option D also occurs in Week 5 and is incorrect<br />
<br />
{Narrowing of a lumen such as the duodenum or the pylorus is also called:<br />
|type="()"}<br />
- duplication<br />
- atresia.<br />
+ stenosis<br />
- gastroschisis<br />
|| Stenosis is the correct answer. Duplication is the incomplete recanalization resulting in parallel lumens, this is really a specialized form of stenosis. Atresia is the interuption of the lumen and gastroschisis is a congenital abdominal wall defect which results in herniation of fetal abdominal viscera into the amniotic cavity.<br />
<br />
</quiz><br />
<br />
[[Student Page]]<br />
<br />
<br />
==Lab 6 Assessment==<br />
<br />
Completed ANAT2341 Lab 5 - Course Feedback Questionnaire</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z5014803&diff=246726
User:Z5014803
2016-09-09T04:49:12Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Student2016}}<br />
<br />
==Lab Attendance==<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 18:29, 5 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:40, 12 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:07, 19 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:09, 26 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:45, 2 September 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:13, 9 September 2016 (AEST)<br />
<br />
<br />
===Belbin Team Roles===<br />
In my previous courses, I was introduced to the Bebin model team roles as a way to identify myself in a team scenario. I definitely see myself as a "Shaper" since I am driven to try and complete the task at hand as soon as possible to ensure sufficient time for the editing process and the refining of the task. I also agree that I motivate other team members to progress through the task at a efficient pace such that the group does not lose momentum. I am also a person who is not afraid to speak my mind and thus will contest other viewpoints in order to spark a discussion. I identify myself as a very dynamic person in the way that I act according to the different predicaments I'm in and this results in numerous ways of efficiently solving any problems. Although I identify myself as a Shape I do not agree that i can become aggressive or bad humoured as I see some traits of a Co-ordinator in me. I have a very mature approach and recognise that each individual has a different way of attacking a problem and have learnt to appreciate others. <br />
<br />
===Lecture 1: Fertilisation===<br />
I have always been fond of the details surrounding fertilisation as it seems like a very interesting topic. It is more than just a sperm and egg cell coming together. The first lecture on fertilisation highlighted the various processes that need to occur in order to form a zygote, from gametogenesis to fertilisation and then forming the zygote. In my first year studies I learnt that there is a mechanism to prevent multiple sperm cells to enter the ovum but wasnt familiar with the process. The most interesting aspect of this lecture was precisely the process from fertilisation to the prevention of polyspermy. I was intrigued by how sperm cells are attracted to the oocyte which was through the ZP2 protein and only the nucleus of the spermatozoa enters the cell membranes. I was also interested in how membrane fusion will result in oocyte processes that will prevent polyspermy through the elevation of intracellular calcium levels. I had minimal knowledge of this topic but the lecture really made me want to learn about this process in a lot more detail. <br />
<br />
==New SubHeading==<br />
===External Link===<br />
[http://www.smh.com.au/ SMH]<br />
<br />
===Internal Link===<br />
[[ANAT2341 Lab 1]]<br />
<br />
[[ANAT2341 Lab 1|Fertilization Lab]]<br />
<br />
[[Student Page]]<br />
<br />
==Referencing==<br />
[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=fertilization fertilization]<br />
<br />
PMID 27486480<br />
<br />
==Assessment 1==<br />
<br />
<pubmed>27486266</pubmed> <br />
<br />
In order for fertilization to occur spermatozoa must be activated in a process known as 'sperm capacitation'. The primary research article "Seminal vesicle proteins SVS3 and SVS4 facilitate SVS2 effect on sperm capacitation" by Araki et al (2016) investigate the role of seminal vesicle secretion and how they inhibit the activation of spermatozoa and how they reduce the fertility of the capacitated spermatozoa (decapacitation). In previous studies it has already been shown that SVS2 acts as a capacitation inhibitor and a decapacitation factor and Araki et al (2016) build up on this pre existent knowledge about SVSs other than SVS2. The investigation utilised CD-1 mice, in particular female mice, to show the effects of SVS3 and SVS4 on sperm cells in the female reproductive tract. <br />
<br />
<br />
Levels of SVS3 and SVS4 were measured in each part of the female reproductive tract such as the copulaatory plug, vagina, oviduct and uterine region near the vagina and oviduct 1.5 hours post copulation. By using anti SVS3 antibody there were clear indications as to the specific roles of SVS3. Results showed that there were no SVS3 proteins in any of the aforementioned parts of the reproductive tract and thus the protein alone had no effects on sperm capacitation. In saying that, SVS3 proteins did show that they had the ability to potentiate the effects of SVS2. Similarly anti SVS4 antibody was utilised to provide insight into the function of this particular protein. Contrary to the findings for SVS3, SVS4 was detected in the uterus but not in any other part of the tract. This suggests that SVS4 has similar activity to that of SVS2 in a way that both the proteins enter the uterus. Thus, SVS4 acts as a capacitation inhibitor similar to SVS2 but results indicated that it does not have the decapacitation effect like SVS2.<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 18 August 2016 - You have added the citation correctly and written a good summary of this very recent article, still only available in the pre-published submitted format, findings. One thing, you must always include the full term in your summary (even if it appears in the paper title) before you begin to use the acronym. "SVS" (seminal vesicle protein secretion) could and may mean different things in different contexts.<br />
<br />
<br />
| width=100px| Assessment 5/5<br />
|}<br />
<br />
==Assessment 2==<br />
<br />
[[File:Development_of_mouse_embryo_in_early_stages.png|400px|thumb|centre|Live imaging of the whole mouse embryo at E6 (A to D) and E5.5. (E to H)<ref><pubmed>23861733</pubmed></ref>]]<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 29 August 2016 - Reference and Copyright correctly included with the file and referenced on your page here. You have not included the <nowiki>{{Student Image}}</nowiki> template in the file summary box.<br />
<br />
| Assessment 4.5/5<br />
|}<br />
<br />
===References===<br />
<br />
<br />
<br />
== Lab 3 Assessment ==<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 31 August 2016 - Lab 3 Assessment Quiz - [[Lecture_-_Mesoderm_Development|Mesoderm]] and [[Lecture_-_Ectoderm_Development|Ectoderm]] development. All correct, Well done!<br />
<br />
| Assessment 5/5<br />
|}<br />
<br />
<br />
==Assessment 4==<br />
==Quiz==<br />
<br />
<quiz display=simple><br />
<br />
{Which of the following structures does the ectoderm contribute to?<br />
|type="()"}<br />
- epithelium, mesentry, connective tissue<br />
+ enteric nervous system<br />
- epithelium and smooth muscle<br />
- enteric nervous system, connective tissue, smooth muscle<br />
|| Option two is correct as the ectoderm only contributes to the enteric nervous system. Epithelium is contributed by the endoderm, whereas the mesentry, connective tissues, smooth muscle, blood vessels are contributed by the mesoderm<br />
<br />
{What lies rostral in relation to the notochord?<br />
|type="()"}<br />
- mesoderm<br />
- the neural tube<br />
+ the buccopharyngeal membrane<br />
- the mesoderm then endoderm<br />
|| The buccopharyngeal membrane lies rostral in relation to the notochord. The mesoderm lies laterally to the notochord, the neural tube dorsally and the mesoderm and endoderm ventrally.<br />
<br />
{During Week 8- 10 (GA 10- 12 weeks):<br />
|type="()"}<br />
+ neural crest migrates into the wall forms enteric nervous system<br />
- endoderm in the GIT wall proliferates<br />
- a second rotation (of 90 degrees) occurs on the longitudinal axis establishing the adult orientation of the stomach.<br />
- mesoderm within the dorsal mesogastrium form a long strip of cells adjacent to the forming stomach above the developing pancreas<br />
|| Option A is correct and is the only one that occurs during weeks 8-10. Option B occurs at the beginning of Week 5. Option C occurs during Week 4. Option D also occurs in Week 5 and is incorrect<br />
<br />
{Narrowing of a lumen such as the duodenum or the pylorus is also called:<br />
|type="()"}<br />
- duplication<br />
- atresia.<br />
+ stenosis<br />
- gastroschisis<br />
|| Stenosis is the correct answer. Duplication is the incomplete recanalization resulting in parallel lumens, this is really a specialized form of stenosis. Atresia is the interuption of the lumen and gastroschisis is a congenital abdominal wall defect which results in herniation of fetal abdominal viscera into the amniotic cavity.<br />
<br />
</quiz><br />
<br />
[[Student Page]]<br />
<br />
==Lab 6 Assessment==<br />
<br />
Completed ANAT2341 Lab 5 - Course Feedback Questionnaire</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z5014803&diff=246638
User:Z5014803
2016-09-09T03:13:41Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Student2016}}<br />
<br />
==Lab Attendance==<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 18:29, 5 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:40, 12 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:07, 19 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:09, 26 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:45, 2 September 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:13, 9 September 2016 (AEST)<br />
<br />
<br />
===Belbin Team Roles===<br />
In my previous courses, I was introduced to the Bebin model team roles as a way to identify myself in a team scenario. I definitely see myself as a "Shaper" since I am driven to try and complete the task at hand as soon as possible to ensure sufficient time for the editing process and the refining of the task. I also agree that I motivate other team members to progress through the task at a efficient pace such that the group does not lose momentum. I am also a person who is not afraid to speak my mind and thus will contest other viewpoints in order to spark a discussion. I identify myself as a very dynamic person in the way that I act according to the different predicaments I'm in and this results in numerous ways of efficiently solving any problems. Although I identify myself as a Shape I do not agree that i can become aggressive or bad humoured as I see some traits of a Co-ordinator in me. I have a very mature approach and recognise that each individual has a different way of attacking a problem and have learnt to appreciate others. <br />
<br />
===Lecture 1: Fertilisation===<br />
I have always been fond of the details surrounding fertilisation as it seems like a very interesting topic. It is more than just a sperm and egg cell coming together. The first lecture on fertilisation highlighted the various processes that need to occur in order to form a zygote, from gametogenesis to fertilisation and then forming the zygote. In my first year studies I learnt that there is a mechanism to prevent multiple sperm cells to enter the ovum but wasnt familiar with the process. The most interesting aspect of this lecture was precisely the process from fertilisation to the prevention of polyspermy. I was intrigued by how sperm cells are attracted to the oocyte which was through the ZP2 protein and only the nucleus of the spermatozoa enters the cell membranes. I was also interested in how membrane fusion will result in oocyte processes that will prevent polyspermy through the elevation of intracellular calcium levels. I had minimal knowledge of this topic but the lecture really made me want to learn about this process in a lot more detail. <br />
<br />
==New SubHeading==<br />
===External Link===<br />
[http://www.smh.com.au/ SMH]<br />
<br />
===Internal Link===<br />
[[ANAT2341 Lab 1]]<br />
<br />
[[ANAT2341 Lab 1|Fertilization Lab]]<br />
<br />
[[Student Page]]<br />
<br />
==Referencing==<br />
[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=fertilization fertilization]<br />
<br />
PMID 27486480<br />
<br />
==Assessment 1==<br />
<br />
<pubmed>27486266</pubmed> <br />
<br />
In order for fertilization to occur spermatozoa must be activated in a process known as 'sperm capacitation'. The primary research article "Seminal vesicle proteins SVS3 and SVS4 facilitate SVS2 effect on sperm capacitation" by Araki et al (2016) investigate the role of seminal vesicle secretion and how they inhibit the activation of spermatozoa and how they reduce the fertility of the capacitated spermatozoa (decapacitation). In previous studies it has already been shown that SVS2 acts as a capacitation inhibitor and a decapacitation factor and Araki et al (2016) build up on this pre existent knowledge about SVSs other than SVS2. The investigation utilised CD-1 mice, in particular female mice, to show the effects of SVS3 and SVS4 on sperm cells in the female reproductive tract. <br />
<br />
<br />
Levels of SVS3 and SVS4 were measured in each part of the female reproductive tract such as the copulaatory plug, vagina, oviduct and uterine region near the vagina and oviduct 1.5 hours post copulation. By using anti SVS3 antibody there were clear indications as to the specific roles of SVS3. Results showed that there were no SVS3 proteins in any of the aforementioned parts of the reproductive tract and thus the protein alone had no effects on sperm capacitation. In saying that, SVS3 proteins did show that they had the ability to potentiate the effects of SVS2. Similarly anti SVS4 antibody was utilised to provide insight into the function of this particular protein. Contrary to the findings for SVS3, SVS4 was detected in the uterus but not in any other part of the tract. This suggests that SVS4 has similar activity to that of SVS2 in a way that both the proteins enter the uterus. Thus, SVS4 acts as a capacitation inhibitor similar to SVS2 but results indicated that it does not have the decapacitation effect like SVS2.<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 18 August 2016 - You have added the citation correctly and written a good summary of this very recent article, still only available in the pre-published submitted format, findings. One thing, you must always include the full term in your summary (even if it appears in the paper title) before you begin to use the acronym. "SVS" (seminal vesicle protein secretion) could and may mean different things in different contexts.<br />
<br />
<br />
| width=100px| Assessment 5/5<br />
|}<br />
<br />
==Assessment 2==<br />
<br />
[[File:Development_of_mouse_embryo_in_early_stages.png|400px|thumb|centre|Live imaging of the whole mouse embryo at E6 (A to D) and E5.5. (E to H)<ref><pubmed>23861733</pubmed></ref>]]<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 29 August 2016 - Reference and Copyright correctly included with the file and referenced on your page here. You have not included the <nowiki>{{Student Image}}</nowiki> template in the file summary box.<br />
<br />
| Assessment 4.5/5<br />
|}<br />
<br />
===References===<br />
<br />
<br />
<br />
== Lab 3 Assessment ==<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 31 August 2016 - Lab 3 Assessment Quiz - [[Lecture_-_Mesoderm_Development|Mesoderm]] and [[Lecture_-_Ectoderm_Development|Ectoderm]] development. All correct, Well done!<br />
<br />
| Assessment 5/5<br />
|}<br />
<br />
<br />
==Assessment 4==<br />
==Quiz==<br />
<br />
<quiz display=simple><br />
<br />
{Which of the following structures does the ectoderm contribute to?<br />
|type="()"}<br />
- epithelium, mesentry, connective tissue<br />
+ enteric nervous system<br />
- epithelium and smooth muscle<br />
- enteric nervous system, connective tissue, smooth muscle<br />
|| Option two is correct as the ectoderm only contributes to the enteric nervous system. Epithelium is contributed by the endoderm, whereas the mesentry, connective tissues, smooth muscle, blood vessels are contributed by the mesoderm<br />
<br />
{What lies rostral in relation to the notochord?<br />
|type="()"}<br />
- mesoderm<br />
- the neural tube<br />
+ the buccopharyngeal membrane<br />
- the mesoderm then endoderm<br />
|| The buccopharyngeal membrane lies rostral in relation to the notochord. The mesoderm lies laterally to the notochord, the neural tube dorsally and the mesoderm and endoderm ventrally.<br />
<br />
{During Week 8- 10 (GA 10- 12 weeks):<br />
|type="()"}<br />
+ neural crest migrates into the wall forms enteric nervous system<br />
- endoderm in the GIT wall proliferates<br />
- a second rotation (of 90 degrees) occurs on the longitudinal axis establishing the adult orientation of the stomach.<br />
- mesoderm within the dorsal mesogastrium form a long strip of cells adjacent to the forming stomach above the developing pancreas<br />
|| Option A is correct and is the only one that occurs during weeks 8-10. Option B occurs at the beginning of Week 5. Option C occurs during Week 4. Option D also occurs in Week 5 and is incorrect<br />
<br />
{Narrowing of a lumen such as the duodenum or the pylorus is also called:<br />
|type="()"}<br />
- duplication<br />
- atresia.<br />
+ stenosis<br />
- gastroschisis<br />
|| Stenosis is the correct answer. Duplication is the incomplete recanalization resulting in parallel lumens, this is really a specialized form of stenosis. Atresia is the interuption of the lumen and gastroschisis is a congenital abdominal wall defect which results in herniation of fetal abdominal viscera into the amniotic cavity.<br />
<br />
</quiz><br />
<br />
[[Student Page]]</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z5014803&diff=245716
User:Z5014803
2016-09-02T04:45:58Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Student2016}}<br />
<br />
==Lab Attendance==<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 18:29, 5 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:40, 12 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:07, 19 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:09, 26 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:45, 2 September 2016 (AEST)<br />
<br />
<br />
===Belbin Team Roles===<br />
In my previous courses, I was introduced to the Bebin model team roles as a way to identify myself in a team scenario. I definitely see myself as a "Shaper" since I am driven to try and complete the task at hand as soon as possible to ensure sufficient time for the editing process and the refining of the task. I also agree that I motivate other team members to progress through the task at a efficient pace such that the group does not lose momentum. I am also a person who is not afraid to speak my mind and thus will contest other viewpoints in order to spark a discussion. I identify myself as a very dynamic person in the way that I act according to the different predicaments I'm in and this results in numerous ways of efficiently solving any problems. Although I identify myself as a Shape I do not agree that i can become aggressive or bad humoured as I see some traits of a Co-ordinator in me. I have a very mature approach and recognise that each individual has a different way of attacking a problem and have learnt to appreciate others. <br />
<br />
===Lecture 1: Fertilisation===<br />
I have always been fond of the details surrounding fertilisation as it seems like a very interesting topic. It is more than just a sperm and egg cell coming together. The first lecture on fertilisation highlighted the various processes that need to occur in order to form a zygote, from gametogenesis to fertilisation and then forming the zygote. In my first year studies I learnt that there is a mechanism to prevent multiple sperm cells to enter the ovum but wasnt familiar with the process. The most interesting aspect of this lecture was precisely the process from fertilisation to the prevention of polyspermy. I was intrigued by how sperm cells are attracted to the oocyte which was through the ZP2 protein and only the nucleus of the spermatozoa enters the cell membranes. I was also interested in how membrane fusion will result in oocyte processes that will prevent polyspermy through the elevation of intracellular calcium levels. I had minimal knowledge of this topic but the lecture really made me want to learn about this process in a lot more detail. <br />
<br />
==New SubHeading==<br />
===External Link===<br />
[http://www.smh.com.au/ SMH]<br />
<br />
===Internal Link===<br />
[[ANAT2341 Lab 1]]<br />
<br />
[[ANAT2341 Lab 1|Fertilization Lab]]<br />
<br />
[[Student Page]]<br />
<br />
==Referencing==<br />
[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=fertilization fertilization]<br />
<br />
PMID 27486480<br />
<br />
==Assessment 1==<br />
<br />
<pubmed>27486266</pubmed> <br />
<br />
In order for fertilization to occur spermatozoa must be activated in a process known as 'sperm capacitation'. The primary research article "Seminal vesicle proteins SVS3 and SVS4 facilitate SVS2 effect on sperm capacitation" by Araki et al (2016) investigate the role of seminal vesicle secretion and how they inhibit the activation of spermatozoa and how they reduce the fertility of the capacitated spermatozoa (decapacitation). In previous studies it has already been shown that SVS2 acts as a capacitation inhibitor and a decapacitation factor and Araki et al (2016) build up on this pre existent knowledge about SVSs other than SVS2. The investigation utilised CD-1 mice, in particular female mice, to show the effects of SVS3 and SVS4 on sperm cells in the female reproductive tract. <br />
<br />
<br />
Levels of SVS3 and SVS4 were measured in each part of the female reproductive tract such as the copulaatory plug, vagina, oviduct and uterine region near the vagina and oviduct 1.5 hours post copulation. By using anti SVS3 antibody there were clear indications as to the specific roles of SVS3. Results showed that there were no SVS3 proteins in any of the aforementioned parts of the reproductive tract and thus the protein alone had no effects on sperm capacitation. In saying that, SVS3 proteins did show that they had the ability to potentiate the effects of SVS2. Similarly anti SVS4 antibody was utilised to provide insight into the function of this particular protein. Contrary to the findings for SVS3, SVS4 was detected in the uterus but not in any other part of the tract. This suggests that SVS4 has similar activity to that of SVS2 in a way that both the proteins enter the uterus. Thus, SVS4 acts as a capacitation inhibitor similar to SVS2 but results indicated that it does not have the decapacitation effect like SVS2.<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 18 August 2016 - You have added the citation correctly and written a good summary of this very recent article, still only available in the pre-published submitted format, findings. One thing, you must always include the full term in your summary (even if it appears in the paper title) before you begin to use the acronym. "SVS" (seminal vesicle protein secretion) could and may mean different things in different contexts.<br />
<br />
<br />
| width=100px| Assessment 5/5<br />
|}<br />
<br />
==Assessment 2==<br />
<br />
[[File:Development_of_mouse_embryo_in_early_stages.png|400px|thumb|centre|Live imaging of the whole mouse embryo at E6 (A to D) and E5.5. (E to H)<ref><pubmed>23861733</pubmed></ref>]]<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 29 August 2016 - Reference and Copyright correctly included with the file and referenced on your page here. You have not included the <nowiki>{{Student Image}}</nowiki> template in the file summary box.<br />
<br />
| Assessment 4.5/5<br />
|}<br />
<br />
===References===<br />
<br />
<br />
<br />
== Lab 3 Assessment ==<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 31 August 2016 - Lab 3 Assessment Quiz - [[Lecture_-_Mesoderm_Development|Mesoderm]] and [[Lecture_-_Ectoderm_Development|Ectoderm]] development. All correct, Well done!<br />
<br />
| Assessment 5/5<br />
|}<br />
<br />
<br />
==Assessment 4==<br />
==Quiz==<br />
<br />
<quiz display=simple><br />
<br />
{Which of the following structures does the ectoderm contribute to?<br />
|type="()"}<br />
- epithelium, mesentry, connective tissue<br />
+ enteric nervous system<br />
- epithelium and smooth muscle<br />
- enteric nervous system, connective tissue, smooth muscle<br />
|| Option two is correct as the ectoderm only contributes to the enteric nervous system. Epithelium is contributed by the endoderm, whereas the mesentry, connective tissues, smooth muscle, blood vessels are contributed by the mesoderm<br />
<br />
{What lies rostral in relation to the notochord?<br />
|type="()"}<br />
- mesoderm<br />
- the neural tube<br />
+ the buccopharyngeal membrane<br />
- the mesoderm then endoderm<br />
|| The buccopharyngeal membrane lies rostral in relation to the notochord. The mesoderm lies laterally to the notochord, the neural tube dorsally and the mesoderm and endoderm ventrally.<br />
<br />
{During Week 8- 10 (GA 10- 12 weeks):<br />
|type="()"}<br />
+ neural crest migrates into the wall forms enteric nervous system<br />
- endoderm in the GIT wall proliferates<br />
- a second rotation (of 90 degrees) occurs on the longitudinal axis establishing the adult orientation of the stomach.<br />
- mesoderm within the dorsal mesogastrium form a long strip of cells adjacent to the forming stomach above the developing pancreas<br />
|| Option A is correct and is the only one that occurs during weeks 8-10. Option B occurs at the beginning of Week 5. Option C occurs during Week 4. Option D also occurs in Week 5 and is incorrect<br />
<br />
{Narrowing of a lumen such as the duodenum or the pylorus is also called:<br />
|type="()"}<br />
- duplication<br />
- atresia.<br />
+ stenosis<br />
- gastroschisis<br />
|| Stenosis is the correct answer. Duplication is the incomplete recanalization resulting in parallel lumens, this is really a specialized form of stenosis. Atresia is the interuption of the lumen and gastroschisis is a congenital abdominal wall defect which results in herniation of fetal abdominal viscera into the amniotic cavity.<br />
<br />
</quiz><br />
<br />
[[Student Page]]</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z5014803&diff=245398
User:Z5014803
2016-09-01T05:14:22Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Student2016}}<br />
<br />
==Lab Attendance==<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 18:29, 5 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:40, 12 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:07, 19 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:09, 26 August 2016 (AEST)<br />
<br />
===Belbin Team Roles===<br />
In my previous courses, I was introduced to the Bebin model team roles as a way to identify myself in a team scenario. I definitely see myself as a "Shaper" since I am driven to try and complete the task at hand as soon as possible to ensure sufficient time for the editing process and the refining of the task. I also agree that I motivate other team members to progress through the task at a efficient pace such that the group does not lose momentum. I am also a person who is not afraid to speak my mind and thus will contest other viewpoints in order to spark a discussion. I identify myself as a very dynamic person in the way that I act according to the different predicaments I'm in and this results in numerous ways of efficiently solving any problems. Although I identify myself as a Shape I do not agree that i can become aggressive or bad humoured as I see some traits of a Co-ordinator in me. I have a very mature approach and recognise that each individual has a different way of attacking a problem and have learnt to appreciate others. <br />
<br />
===Lecture 1: Fertilisation===<br />
I have always been fond of the details surrounding fertilisation as it seems like a very interesting topic. It is more than just a sperm and egg cell coming together. The first lecture on fertilisation highlighted the various processes that need to occur in order to form a zygote, from gametogenesis to fertilisation and then forming the zygote. In my first year studies I learnt that there is a mechanism to prevent multiple sperm cells to enter the ovum but wasnt familiar with the process. The most interesting aspect of this lecture was precisely the process from fertilisation to the prevention of polyspermy. I was intrigued by how sperm cells are attracted to the oocyte which was through the ZP2 protein and only the nucleus of the spermatozoa enters the cell membranes. I was also interested in how membrane fusion will result in oocyte processes that will prevent polyspermy through the elevation of intracellular calcium levels. I had minimal knowledge of this topic but the lecture really made me want to learn about this process in a lot more detail. <br />
<br />
==New SubHeading==<br />
===External Link===<br />
[http://www.smh.com.au/ SMH]<br />
<br />
===Internal Link===<br />
[[ANAT2341 Lab 1]]<br />
<br />
[[ANAT2341 Lab 1|Fertilization Lab]]<br />
<br />
[[Student Page]]<br />
<br />
==Referencing==<br />
[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=fertilization fertilization]<br />
<br />
PMID 27486480<br />
<br />
==Assessment 1==<br />
<br />
<pubmed>27486266</pubmed> <br />
<br />
In order for fertilization to occur spermatozoa must be activated in a process known as 'sperm capacitation'. The primary research article "Seminal vesicle proteins SVS3 and SVS4 facilitate SVS2 effect on sperm capacitation" by Araki et al (2016) investigate the role of seminal vesicle secretion and how they inhibit the activation of spermatozoa and how they reduce the fertility of the capacitated spermatozoa (decapacitation). In previous studies it has already been shown that SVS2 acts as a capacitation inhibitor and a decapacitation factor and Araki et al (2016) build up on this pre existent knowledge about SVSs other than SVS2. The investigation utilised CD-1 mice, in particular female mice, to show the effects of SVS3 and SVS4 on sperm cells in the female reproductive tract. <br />
<br />
<br />
Levels of SVS3 and SVS4 were measured in each part of the female reproductive tract such as the copulaatory plug, vagina, oviduct and uterine region near the vagina and oviduct 1.5 hours post copulation. By using anti SVS3 antibody there were clear indications as to the specific roles of SVS3. Results showed that there were no SVS3 proteins in any of the aforementioned parts of the reproductive tract and thus the protein alone had no effects on sperm capacitation. In saying that, SVS3 proteins did show that they had the ability to potentiate the effects of SVS2. Similarly anti SVS4 antibody was utilised to provide insight into the function of this particular protein. Contrary to the findings for SVS3, SVS4 was detected in the uterus but not in any other part of the tract. This suggests that SVS4 has similar activity to that of SVS2 in a way that both the proteins enter the uterus. Thus, SVS4 acts as a capacitation inhibitor similar to SVS2 but results indicated that it does not have the decapacitation effect like SVS2.<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 18 August 2016 - You have added the citation correctly and written a good summary of this very recent article, still only available in the pre-published submitted format, findings. One thing, you must always include the full term in your summary (even if it appears in the paper title) before you begin to use the acronym. "SVS" (seminal vesicle protein secretion) could and may mean different things in different contexts.<br />
<br />
<br />
| width=100px| Assessment 5/5<br />
|}<br />
<br />
==Assessment 2==<br />
<br />
[[File:Development_of_mouse_embryo_in_early_stages.png|400px|thumb|centre|Live imaging of the whole mouse embryo at E6 (A to D) and E5.5. (E to H)<ref><pubmed>23861733</pubmed></ref>]]<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 29 August 2016 - Reference and Copyright correctly included with the file and referenced on your page here. You have not included the <nowiki>{{Student Image}}</nowiki> template in the file summary box.<br />
<br />
| Assessment 4.5/5<br />
|}<br />
<br />
===References===<br />
<br />
<br />
<br />
== Lab 3 Assessment ==<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 31 August 2016 - Lab 3 Assessment Quiz - [[Lecture_-_Mesoderm_Development|Mesoderm]] and [[Lecture_-_Ectoderm_Development|Ectoderm]] development. All correct, Well done!<br />
<br />
| Assessment 5/5<br />
|}<br />
<br />
<br />
==Assessment 4==<br />
==Quiz==<br />
<br />
<quiz display=simple><br />
<br />
{Which of the following structures does the ectoderm contribute to?<br />
|type="()"}<br />
- epithelium, mesentry, connective tissue<br />
+ enteric nervous system<br />
- epithelium and smooth muscle<br />
- enteric nervous system, connective tissue, smooth muscle<br />
|| Option two is correct as the ectoderm only contributes to the enteric nervous system. Epithelium is contributed by the endoderm, whereas the mesentry, connective tissues, smooth muscle, blood vessels are contributed by the mesoderm<br />
<br />
{What lies rostral in relation to the notochord?<br />
|type="()"}<br />
- mesoderm<br />
- the neural tube<br />
+ the buccopharyngeal membrane<br />
- the mesoderm then endoderm<br />
|| The buccopharyngeal membrane lies rostral in relation to the notochord. The mesoderm lies laterally to the notochord, the neural tube dorsally and the mesoderm and endoderm ventrally.<br />
<br />
{During Week 8- 10 (GA 10- 12 weeks):<br />
|type="()"}<br />
+ neural crest migrates into the wall forms enteric nervous system<br />
- endoderm in the GIT wall proliferates<br />
- a second rotation (of 90 degrees) occurs on the longitudinal axis establishing the adult orientation of the stomach.<br />
- mesoderm within the dorsal mesogastrium form a long strip of cells adjacent to the forming stomach above the developing pancreas<br />
|| Option A is correct and is the only one that occurs during weeks 8-10. Option B occurs at the beginning of Week 5. Option C occurs during Week 4. Option D also occurs in Week 5 and is incorrect<br />
<br />
{Narrowing of a lumen such as the duodenum or the pylorus is also called:<br />
|type="()"}<br />
- duplication<br />
- atresia.<br />
+ stenosis<br />
- gastroschisis<br />
|| Stenosis is the correct answer. Duplication is the incomplete recanalization resulting in parallel lumens, this is really a specialized form of stenosis. Atresia is the interuption of the lumen and gastroschisis is a congenital abdominal wall defect which results in herniation of fetal abdominal viscera into the amniotic cavity.<br />
<br />
<br />
[[Student Page]]</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2016_Group_Project_2&diff=244330
Talk:2016 Group Project 2
2016-08-26T04:54:11Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016discussionheader}}<br />
<br />
<br />
<br />
<br />
[[User:Z3462474|Z3462474]] ([[User talk:Z3462474|talk]]) 14:27, 26 August 2016 (AEST) Here are some reviews I have found that could be a helpful starting point: <br />
<br />
Notch signalling at a glance: http://jcs.biologists.org/content/joces/126/10/2135.full.pdf <br />
<br />
Signalling pathways for neural development: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369499/pdf/WJSC-7-437.pdf<br />
<br />
Notch's role in diabetic neuropathy https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677813/pdf/nihms473246.pdf<br />
<br />
Notch in cardio development and disease http://circres.ahajournals.org/content/118/1/e1.full<br />
<br />
[[User:Z5015014|Z5015014]] ([[User talk:Z5015014|talk]]) 14:28, 26 August 2016 (AEST) here's the embryology site page for [[Developmental Signals - Notch|Notch signalling]]!<br />
<br />
[[User:Z5015014|Z5015014]] ([[User talk:Z5015014|talk]]) 14:31, 26 August 2016 (AEST) I also found a review article for Notch signalling in the common fruit fly, which could be a good idea for a subsection: PMID 12369105 ''General outlines of the molecular genetics of the Notch signalling pathway in Drosophila melanogaster: a review''.<br />
<br />
[[User:Z5015014|Z5015014]] ([[User talk:Z5015014|talk]]) 14:44, 26 August 2016 (AEST) and here's some more reviews: PMID 22397947 ''Non-canonical Notch signaling: emerging role and mechanism'' and PMID 21828089 ''Notch signaling: simplicity in design, versatility in function''.<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]])<br />
https://www.researchgate.net/publication/264164124_Introduction_to_Notch_Signaling This seems like a good link for the history and discovery of the pathway<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]])<br />
https://embryo.asu.edu/pages/notch-signaling-pathway-embryogenesis Can be used for introduction<br />
<br />
<br />
<br />
[[User:Z3462474|Z3462474]] ([[User talk:Z3462474|talk]]) 12:41, 19 August 2016 (AEST) Signalling in neural embryonic development looks interesting! Particularly the paper about NSCs and psychiatric disorders.<br />
<br />
[[User:Z5015014|Z5015014]] ([[User talk:Z5015014|talk]]) 21:59, 18 August 2016 (AEST): Hedgehog signalling (specifically SHH signalling) sounds really interesting!<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 22:39, 18 August 2016 (AEST): Bone Morphogenetic Proteins (BMP) signalling in development looks interesting<br />
<br />
[[User:Z3491219|Z3491219]] ([[User talk:Z3491219|talk]]) I think looking at how in utero exposure to cigarette smoke affects fetal ovarian development signalling would be interesting.</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=2016_Group_Project_2&diff=244308
2016 Group Project 2
2016-08-26T04:51:04Z
<p>Z5014803: /* Notch signalling pathway */</p>
<hr />
<div>{{ANAT2341Project2016header}}<br />
{{Group Assessment Criteria table}}<br />
<!-- Do not delete the above template from the Group project page. --><br />
<br />
==Notch signalling pathway==<br />
<br />
===Introduction===<br />
<br />
===History===</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2016_Group_Project_2&diff=244280
Talk:2016 Group Project 2
2016-08-26T04:42:15Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016discussionheader}}<br />
<br />
<br />
[[User:Z3462474|Z3462474]] ([[User talk:Z3462474|talk]]) 14:27, 26 August 2016 (AEST) Here are some reviews I have found that could be a helpful starting point: <br />
<br />
Notch signalling at a glance: http://jcs.biologists.org/content/joces/126/10/2135.full.pdf <br />
<br />
Signalling pathways for neural development: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369499/pdf/WJSC-7-437.pdf<br />
<br />
Notch's role in diabetic neuropathy https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677813/pdf/nihms473246.pdf<br />
<br />
Notch in cardio development and disease http://circres.ahajournals.org/content/118/1/e1.full<br />
<br />
[[User:Z5015014|Z5015014]] ([[User talk:Z5015014|talk]]) 14:28, 26 August 2016 (AEST) here's the embryology site page for [[Developmental Signals - Notch|Notch signalling]]!<br />
<br />
[[User:Z5015014|Z5015014]] ([[User talk:Z5015014|talk]]) 14:31, 26 August 2016 (AEST) I also found a review article for Notch signalling in the common fruit fly, which could be a good idea for a subsection: PMID 12369105 ''General outlines of the molecular genetics of the Notch signalling pathway in Drosophila melanogaster: a review''.<br />
<br />
https://www.researchgate.net/publication/264164124_Introduction_to_Notch_Signaling This seems like a good link for the history and discovery of the pathway<br />
<br />
<br />
<br />
[[User:Z3462474|Z3462474]] ([[User talk:Z3462474|talk]]) 12:41, 19 August 2016 (AEST) Signalling in neural embryonic development looks interesting! Particularly the paper about NSCs and psychiatric disorders.<br />
<br />
[[User:Z5015014|Z5015014]] ([[User talk:Z5015014|talk]]) 21:59, 18 August 2016 (AEST): Hedgehog signalling (specifically SHH signalling) sounds really interesting!<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 22:39, 18 August 2016 (AEST): Bone Morphogenetic Proteins (BMP) signalling in development looks interesting<br />
<br />
[[User:Z3491219|Z3491219]] ([[User talk:Z3491219|talk]]) I think looking at how in utero exposure to cigarette smoke affects fetal ovarian development signalling would be interesting.</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z5014803&diff=244144
User:Z5014803
2016-08-26T03:09:20Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Student2016}}<br />
<br />
==Lab Attendance==<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 18:29, 5 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:40, 12 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:07, 19 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 13:09, 26 August 2016 (AEST)<br />
<br />
===Belbin Team Roles===<br />
In my previous courses, I was introduced to the Bebin model team roles as a way to identify myself in a team scenario. I definitely see myself as a "Shaper" since I am driven to try and complete the task at hand as soon as possible to ensure sufficient time for the editing process and the refining of the task. I also agree that I motivate other team members to progress through the task at a efficient pace such that the group does not lose momentum. I am also a person who is not afraid to speak my mind and thus will contest other viewpoints in order to spark a discussion. I identify myself as a very dynamic person in the way that I act according to the different predicaments I'm in and this results in numerous ways of efficiently solving any problems. Although I identify myself as a Shape I do not agree that i can become aggressive or bad humoured as I see some traits of a Co-ordinator in me. I have a very mature approach and recognise that each individual has a different way of attacking a problem and have learnt to appreciate others. <br />
<br />
===Lecture 1: Fertilisation===<br />
I have always been fond of the details surrounding fertilisation as it seems like a very interesting topic. It is more than just a sperm and egg cell coming together. The first lecture on fertilisation highlighted the various processes that need to occur in order to form a zygote, from gametogenesis to fertilisation and then forming the zygote. In my first year studies I learnt that there is a mechanism to prevent multiple sperm cells to enter the ovum but wasnt familiar with the process. The most interesting aspect of this lecture was precisely the process from fertilisation to the prevention of polyspermy. I was intrigued by how sperm cells are attracted to the oocyte which was through the ZP2 protein and only the nucleus of the spermatozoa enters the cell membranes. I was also interested in how membrane fusion will result in oocyte processes that will prevent polyspermy through the elevation of intracellular calcium levels. I had minimal knowledge of this topic but the lecture really made me want to learn about this process in a lot more detail. <br />
<br />
==New SubHeading==<br />
===External Link===<br />
[http://www.smh.com.au/ SMH]<br />
<br />
===Internal Link===<br />
[[ANAT2341 Lab 1]]<br />
<br />
[[ANAT2341 Lab 1|Fertilization Lab]]<br />
<br />
[[Student Page]]<br />
<br />
==Referencing==<br />
[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=fertilization fertilization]<br />
<br />
PMID 27486480<br />
<br />
==Assessment 1==<br />
<br />
<pubmed>27486266</pubmed> <br />
<br />
In order for fertilization to occur spermatozoa must be activated in a process known as 'sperm capacitation'. The primary research article "Seminal vesicle proteins SVS3 and SVS4 facilitate SVS2 effect on sperm capacitation" by Araki et al (2016) investigate the role of seminal vesicle secretion and how they inhibit the activation of spermatozoa and how they reduce the fertility of the capacitated spermatozoa (decapacitation). In previous studies it has already been shown that SVS2 acts as a capacitation inhibitor and a decapacitation factor and Araki et al (2016) build up on this pre existent knowledge about SVSs other than SVS2. The investigation utilised CD-1 mice, in particular female mice, to show the effects of SVS3 and SVS4 on sperm cells in the female reproductive tract. <br />
<br />
<br />
Levels of SVS3 and SVS4 were measured in each part of the female reproductive tract such as the copulaatory plug, vagina, oviduct and uterine region near the vagina and oviduct 1.5 hours post copulation. By using anti SVS3 antibody there were clear indications as to the specific roles of SVS3. Results showed that there were no SVS3 proteins in any of the aforementioned parts of the reproductive tract and thus the protein alone had no effects on sperm capacitation. In saying that, SVS3 proteins did show that they had the ability to potentiate the effects of SVS2. Similarly anti SVS4 antibody was utilised to provide insight into the function of this particular protein. Contrary to the findings for SVS3, SVS4 was detected in the uterus but not in any other part of the tract. This suggests that SVS4 has similar activity to that of SVS2 in a way that both the proteins enter the uterus. Thus, SVS4 acts as a capacitation inhibitor similar to SVS2 but results indicated that it does not have the decapacitation effect like SVS2.<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 18 August 2016 - You have added the citation correctly and written a good summary of this very recent article, still only available in the pre-published submitted format, findings. One thing, you must always include the full term in your summary (even if it appears in the paper title) before you begin to use the acronym. "SVS" (seminal vesicle protein secretion) could and may mean different things in different contexts.<br />
<br />
<br />
| width=100px| Assessment 5/5<br />
|}<br />
<br />
==Assessment 2==<br />
<br />
[[File:Development_of_mouse_embryo_in_early_stages.png|400px|thumb|centre|Live imaging of the whole mouse embryo at E6 (A to D) and E5.5. (E to H)<ref><pubmed>23861733</pubmed></ref>]]<br />
<br />
===References===</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z5014803&diff=242547
User:Z5014803
2016-08-19T04:07:22Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Student2016}}<br />
<br />
==Lab Attendance==<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 18:29, 5 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:40, 12 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:07, 19 August 2016 (AEST)<br />
<br />
===Belbin Team Roles===<br />
In my previous courses, I was introduced to the Bebin model team roles as a way to identify myself in a team scenario. I definitely see myself as a "Shaper" since I am driven to try and complete the task at hand as soon as possible to ensure sufficient time for the editing process and the refining of the task. I also agree that I motivate other team members to progress through the task at a efficient pace such that the group does not lose momentum. I am also a person who is not afraid to speak my mind and thus will contest other viewpoints in order to spark a discussion. I identify myself as a very dynamic person in the way that I act according to the different predicaments I'm in and this results in numerous ways of efficiently solving any problems. Although I identify myself as a Shape I do not agree that i can become aggressive or bad humoured as I see some traits of a Co-ordinator in me. I have a very mature approach and recognise that each individual has a different way of attacking a problem and have learnt to appreciate others. <br />
<br />
===Lecture 1: Fertilisation===<br />
I have always been fond of the details surrounding fertilisation as it seems like a very interesting topic. It is more than just a sperm and egg cell coming together. The first lecture on fertilisation highlighted the various processes that need to occur in order to form a zygote, from gametogenesis to fertilisation and then forming the zygote. In my first year studies I learnt that there is a mechanism to prevent multiple sperm cells to enter the ovum but wasnt familiar with the process. The most interesting aspect of this lecture was precisely the process from fertilisation to the prevention of polyspermy. I was intrigued by how sperm cells are attracted to the oocyte which was through the ZP2 protein and only the nucleus of the spermatozoa enters the cell membranes. I was also interested in how membrane fusion will result in oocyte processes that will prevent polyspermy through the elevation of intracellular calcium levels. I had minimal knowledge of this topic but the lecture really made me want to learn about this process in a lot more detail. <br />
<br />
==New SubHeading==<br />
===External Link===<br />
[http://www.smh.com.au/ SMH]<br />
<br />
===Internal Link===<br />
[[ANAT2341 Lab 1]]<br />
<br />
[[ANAT2341 Lab 1|Fertilization Lab]]<br />
<br />
[[Student Page]]<br />
<br />
==Referencing==<br />
[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=fertilization fertilization]<br />
<br />
PMID 27486480<br />
<br />
==Assessment 1==<br />
<br />
<pubmed>27486266</pubmed> <br />
<br />
In order for fertilization to occur spermatozoa must be activated in a process known as 'sperm capacitation'. The primary research article "Seminal vesicle proteins SVS3 and SVS4 facilitate SVS2 effect on sperm capacitation" by Araki et al (2016) investigate the role of seminal vesicle secretion and how they inhibit the activation of spermatozoa and how they reduce the fertility of the capacitated spermatozoa (decapacitation). In previous studies it has already been shown that SVS2 acts as a capacitation inhibitor and a decapacitation factor and Araki et al (2016) build up on this pre existent knowledge about SVSs other than SVS2. The investigation utilised CD-1 mice, in particular female mice, to show the effects of SVS3 and SVS4 on sperm cells in the female reproductive tract. <br />
<br />
<br />
Levels of SVS3 and SVS4 were measured in each part of the female reproductive tract such as the copulaatory plug, vagina, oviduct and uterine region near the vagina and oviduct 1.5 hours post copulation. By using anti SVS3 antibody there were clear indications as to the specific roles of SVS3. Results showed that there were no SVS3 proteins in any of the aforementioned parts of the reproductive tract and thus the protein alone had no effects on sperm capacitation. In saying that, SVS3 proteins did show that they had the ability to potentiate the effects of SVS2. Similarly anti SVS4 antibody was utilised to provide insight into the function of this particular protein. Contrary to the findings for SVS3, SVS4 was detected in the uterus but not in any other part of the tract. This suggests that SVS4 has similar activity to that of SVS2 in a way that both the proteins enter the uterus. Thus, SVS4 acts as a capacitation inhibitor similar to SVS2 but results indicated that it does not have the decapacitation effect like SVS2.<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 18 August 2016 - You have added the citation correctly and written a good summary of this very recent article, still only available in the pre-published submitted format, findings. One thing, you must always include the full term in your summary (even if it appears in the paper title) before you begin to use the acronym. "SVS" (seminal vesicle protein secretion) could and may mean different things in different contexts.<br />
<br />
<br />
| width=100px| Assessment 5/5<br />
|}<br />
<br />
==Assessment 2==<br />
<br />
[[File:Development_of_mouse_embryo_in_early_stages.png|400px|thumb|centre|Live imaging of the whole mouse embryo at E6 (A to D) and E5.5. (E to H)<ref><pubmed>23861733</pubmed></ref>]]<br />
<br />
===References===</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=2016_Group_Project_2&diff=242183
2016 Group Project 2
2016-08-18T13:11:55Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016header}}<br />
<!-- Do not delete the above template from the Group project page. --><br />
<br />
[[User:Z5015014|Z5015014]] ([[User talk:Z5015014|talk]]) 21:59, 18 August 2016 (AEST): Hedgehog signalling (specifically SHH signalling) sounds really interesting!<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 22:39, 18 August 2016 (AEST): Bone Morphogenetic Proteins (BMP) signalling in development looks interesting</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=2016_Group_Project_2&diff=242181
2016 Group Project 2
2016-08-18T13:11:41Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016header}}<br />
<!-- Do not delete the above template from the Group project page. --><br />
<br />
[[User:Z5015014|Z5015014]] ([[User talk:Z5015014|talk]]) 21:59, 18 August 2016 (AEST): Hedgehog signalling (specifically SHH signalling) sounds really interesting!<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 22:39, 18 August 2016 (AEST): Bone Morphogenetic Proteins (BMP) signalling in development look interesting</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=2016_Group_Project_2&diff=242179
2016 Group Project 2
2016-08-18T13:10:54Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016header}}<br />
<!-- Do not delete the above template from the Group project page. --><br />
<br />
[[User:Z5015014|Z5015014]] ([[User talk:Z5015014|talk]]) 21:59, 18 August 2016 (AEST): Hedgehog signalling (specifically SHH signalling) sounds really interesting!<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 22:39, 18 August 2016 (AEST): Bone Morphogenetic Proteins (BMP) look interesting</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=2016_Group_Project_2&diff=242177
2016 Group Project 2
2016-08-18T13:04:10Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Project2016header}}<br />
<!-- Do not delete the above template from the Group project page. --><br />
<br />
[[User:Z5015014|Z5015014]] ([[User talk:Z5015014|talk]]) 21:59, 18 August 2016 (AEST): Hedgehog signalling (specifically SHH signalling) sounds really interesting!<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 22:39, 18 August 2016 (AEST): Abnormalities that can occur during pregnancy (Any stage from fertilisation to delivery)</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Development_of_mouse_embryo_in_early_stages.png&diff=242129
File:Development of mouse embryo in early stages.png
2016-08-18T12:14:53Z
<p>Z5014803: </p>
<hr />
<div>==Imaging of mouse embryos at E5.5 and E6==<br />
<br />
(A and E) Each image represents the maximum intensity projection of a 13-µm thick section. Scale bar = 20 µm. (B and F) Annotated sections are 65 (B) and 40 (E) µm from the distal end of the embryo. Blue and green areas indicate visceral endoderm and epiblast, respectively. (C and G) INM and INM-like movement in the epiblast. The colored nucleus exhibits apical migration. (D and H) Image of sections stained with Alexa Fluor 546 phalloidin (membrane) and DRAQ5 (nucleus).<br />
<br />
z5014803<br />
<br />
http://dx.doi.org/10.1371/journal.pone.0064506.g003<br />
<br />
===References===<br />
<pubmed>23861733</pubmed><br />
<br />
===Copyright===<br />
© 2013 Ichikawa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Development_of_mouse_embryo_in_early_stages.png&diff=242127
File:Development of mouse embryo in early stages.png
2016-08-18T12:13:50Z
<p>Z5014803: </p>
<hr />
<div>==Imaging of mouse embryos at E5.5 and E6==<br />
<br />
(A and E) Each image represents the maximum intensity projection of a 13-µm thick section. Scale bar = 20 µm. (B and F) Annotated sections are 65 (B) and 40 (E) µm from the distal end of the embryo. Blue and green areas indicate visceral endoderm and epiblast, respectively. (C and G) INM and INM-like movement in the epiblast. The colored nucleus exhibits apical migration. (D and H) Image of sections stained with Alexa Fluor 546 phalloidin (membrane) and DRAQ5 (nucleus).<br />
<br />
z5014803<br />
<br />
http://dx.doi.org/10.1371/journal.pone.0064506.g003<br />
<br />
===References===<br />
<pubmed>23861733</pubmed><br />
<br />
==Copyright==<br />
© 2013 Ichikawa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Development_of_mouse_embryo_in_early_stages.png&diff=242119
File:Development of mouse embryo in early stages.png
2016-08-18T12:11:08Z
<p>Z5014803: </p>
<hr />
<div>==Imaging of mouse embryos at E5.5 and E6==<br />
<br />
(A and E) Each image represents the maximum intensity projection of a 13-µm thick section. Scale bar = 20 µm. (B and F) Annotated sections are 65 (B) and 40 (E) µm from the distal end of the embryo. Blue and green areas indicate visceral endoderm and epiblast, respectively. (C and G) INM and INM-like movement in the epiblast. The colored nucleus exhibits apical migration. (D and H) Image of sections stained with Alexa Fluor 546 phalloidin (membrane) and DRAQ5 (nucleus).<br />
<br />
http://dx.doi.org/10.1371/journal.pone.0064506.g003<br />
<br />
===References===<br />
<pubmed>23861733</pubmed><br />
<br />
==Copyright==<br />
© 2013 Ichikawa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</div>
Z5014803
https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z5014803&diff=242105
User:Z5014803
2016-08-18T12:04:43Z
<p>Z5014803: </p>
<hr />
<div>{{ANAT2341Student2016}}<br />
<br />
==Lab Attendance==<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 18:29, 5 August 2016 (AEST)<br />
<br />
[[User:Z5014803|Z5014803]] ([[User talk:Z5014803|talk]]) 14:40, 12 August 2016 (AEST)<br />
<br />
===Belbin Team Roles===<br />
In my previous courses, I was introduced to the Bebin model team roles as a way to identify myself in a team scenario. I definitely see myself as a "Shaper" since I am driven to try and complete the task at hand as soon as possible to ensure sufficient time for the editing process and the refining of the task. I also agree that I motivate other team members to progress through the task at a efficient pace such that the group does not lose momentum. I am also a person who is not afraid to speak my mind and thus will contest other viewpoints in order to spark a discussion. I identify myself as a very dynamic person in the way that I act according to the different predicaments I'm in and this results in numerous ways of efficiently solving any problems. Although I identify myself as a Shape I do not agree that i can become aggressive or bad humoured as I see some traits of a Co-ordinator in me. I have a very mature approach and recognise that each individual has a different way of attacking a problem and have learnt to appreciate others. <br />
<br />
===Lecture 1: Fertilisation===<br />
I have always been fond of the details surrounding fertilisation as it seems like a very interesting topic. It is more than just a sperm and egg cell coming together. The first lecture on fertilisation highlighted the various processes that need to occur in order to form a zygote, from gametogenesis to fertilisation and then forming the zygote. In my first year studies I learnt that there is a mechanism to prevent multiple sperm cells to enter the ovum but wasnt familiar with the process. The most interesting aspect of this lecture was precisely the process from fertilisation to the prevention of polyspermy. I was intrigued by how sperm cells are attracted to the oocyte which was through the ZP2 protein and only the nucleus of the spermatozoa enters the cell membranes. I was also interested in how membrane fusion will result in oocyte processes that will prevent polyspermy through the elevation of intracellular calcium levels. I had minimal knowledge of this topic but the lecture really made me want to learn about this process in a lot more detail. <br />
<br />
==New SubHeading==<br />
===External Link===<br />
[http://www.smh.com.au/ SMH]<br />
<br />
===Internal Link===<br />
[[ANAT2341 Lab 1]]<br />
<br />
[[ANAT2341 Lab 1|Fertilization Lab]]<br />
<br />
[[Student Page]]<br />
<br />
==Referencing==<br />
[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=fertilization fertilization]<br />
<br />
PMID 27486480<br />
<br />
==Assessment 1==<br />
<br />
<pubmed>27486266</pubmed> <br />
<br />
In order for fertilization to occur spermatozoa must be activated in a process known as 'sperm capacitation'. The primary research article "Seminal vesicle proteins SVS3 and SVS4 facilitate SVS2 effect on sperm capacitation" by Araki et al (2016) investigate the role of seminal vesicle secretion and how they inhibit the activation of spermatozoa and how they reduce the fertility of the capacitated spermatozoa (decapacitation). In previous studies it has already been shown that SVS2 acts as a capacitation inhibitor and a decapacitation factor and Araki et al (2016) build up on this pre existent knowledge about SVSs other than SVS2. The investigation utilised CD-1 mice, in particular female mice, to show the effects of SVS3 and SVS4 on sperm cells in the female reproductive tract. <br />
<br />
<br />
Levels of SVS3 and SVS4 were measured in each part of the female reproductive tract such as the copulaatory plug, vagina, oviduct and uterine region near the vagina and oviduct 1.5 hours post copulation. By using anti SVS3 antibody there were clear indications as to the specific roles of SVS3. Results showed that there were no SVS3 proteins in any of the aforementioned parts of the reproductive tract and thus the protein alone had no effects on sperm capacitation. In saying that, SVS3 proteins did show that they had the ability to potentiate the effects of SVS2. Similarly anti SVS4 antibody was utilised to provide insight into the function of this particular protein. Contrary to the findings for SVS3, SVS4 was detected in the uterus but not in any other part of the tract. This suggests that SVS4 has similar activity to that of SVS2 in a way that both the proteins enter the uterus. Thus, SVS4 acts as a capacitation inhibitor similar to SVS2 but results indicated that it does not have the decapacitation effect like SVS2.<br />
<br />
<br />
{| width=95%<br />
|-bgcolor="FAF5FF"<br />
| [mailto:m.hill@unsw.edu.au Mark Hill] 18 August 2016 - You have added the citation correctly and written a good summary of this very recent article, still only available in the pre-published submitted format, findings. One thing, you must always include the full term in your summary (even if it appears in the paper title) before you begin to use the acronym. "SVS" (seminal vesicle protein secretion) could and may mean different things in different contexts.<br />
<br />
<br />
| width=100px| Assessment 5/5<br />
|}<br />
<br />
==Assessment 2==<br />
<br />
[[File:Development_of_mouse_embryo_in_early_stages.png|400px|thumb|centre|Live imaging of the whole mouse embryo at E6 (A to D) and E5.5. (E to H)<ref><pubmed>23861733</pubmed></ref>]]<br />
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===References===</div>
Z5014803