1 and 2 respectively mark the endodermal side of pharyngeal arches one and two and Ht shows where the heart lies in the embryo.

The image shows the pharyngeal arches one and two in mice embryo. All three layers ectoderm, mesoderm and endoderm from arch one and two contribute to the formation of the ear.

<pubmed>22110697</pubmed>

Citation: Diman NYS-G, Remacle S, Bertrand N, Picard JJ, Zaffran S, et al. (2011) A Retinoic Acid Responsive Hoxa3 Transgene Expressed in Embryonic Pharyngeal Endoderm, Cardiac Neural Crest and a Subdomain of the Second Heart Field. PLoS ONE 6(11): e27624. doi:10.1371/journal.pone.0027624

Copyright: © 2011 Diman 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.

{{template:Student Image}}

File:Pharyngeal arch one and two in mice.png

2012-10-03T00:31:37Z

Z3333794:

File:Sox9.png

2012-10-02T11:54:49Z

User talk:Z3333794

2012-10-02T11:45:25Z

Z3333794:

User:Z3333794

2012-10-02T11:44:03Z

Z3333794: /* Lab 9 */

==Lab Attendance==
'''Lab 1''' --[[User:Z3333794|Z3333794]] 10:59, 25 July 2012 (EST)

'''Lab 2''' --[[User:Z3333794|Z3333794]] 10:02, 1 August 2012 (EST)

'''Lab 3''' --[[User:Z3333794|Z3333794]] 10:10, 8 August 2012 (EST)

'''Lab 4''' --[[User:Z3333794|Z3333794]] 10:04, 15 August 2012 (EST)

'''Lab 5''' --[[User:Z3333794|Z3333794]] 09:49, 22 August 2012 (EST)

'''Lab 6''' --[[User:Z3333794|Z3333794]] 10:07, 29 August 2012 (EST)

'''Lab 7''' --[[User:Z3333794|Z3333794]] 10:07, 12 September 2012 (EST)

'''Lab 8''' --[[User:Z3333794|Z3333794]] 10:04, 19 September 2012 (EST)

'''Lab 9''' --[[User:Z3333794|Z3333794]] 10:01, 26 September 2012 (EST)

==Lab Exercises==

===Lab 1===

'''Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.'''

The roots of InVitro Fertilization (IVF) and Embryo Transfer (ET) dates back to the early 1890s where Walter Heape a dedicated professor and physician at the University of Cambridge in England whereby he reported the first case of embryo transplant in rabbits. He then went on to do more research in the field of reproduction on a variety of animal species. [http://www.ivf-worldwide.com/ivf-history.html IVF history]

IVF worldwide also articulates that the first in vitro fertilization of human oocytes was carried out in 1965 in John Hopkins Hospital, USA by Edwards and Jones and the first IVF pregnancy occurred in 1973 in the Melbourne, Australia by researchers Wood and Leeton. The pregnancy led to a miscarriage and the first IVF baby was born in England on 25th July 1978, 5 years later. [http://www.ivf-worldwide.com/ivf-history.html IVF history]

The 2010 Nobel prize in Physiology and Medicine was awarded to Robert G. Edwards for development of in vitro Fertilization. His contribution to embryology made a worldwide impact as it became a viable way to overcome infertility. [[http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/|Link Nobel Prize Winner 2010]]

'''Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).'''

In Vitro Fertilization technology has not only impacted humans as a way to overcome infertility but has majot implications for the animal society as well. It is used in breeding practices throughout the world to breed the best quality animals. To make sure the treatment is cost effective it is imperative that the process of IVF leads to a successful pregnancy and as a result birth. Research carried by Jimenez et.al., 2011 focuses at investigating the link between thickness of zona pellucida fertilization, embryo implantation and birth. By using video chromatography their team successfully concluded that the thickness of zona pelucida greatly impacted the fertilization process and transplantation but did not significantly impact in birth.

<pubmed> 22607772 </pubmed>

===Lab 2===

====Adding an Image with the class====

[[File:GnRH receptors (GnRHRs) and spatial expression patterns of gnrhr genes.png|500px]]

====Online Lab Questions====

'''Upload an image from a journal source relating to fertilization or the first 2 weeks of development.'''

[[File:Expression of CD82 in human placental villi and cell lines.JPG]]

'''Identify a protein associated with the implantation process, including a brief description of the protein's role.'''

The Rac-1 protein [[http://www.ncbi.nlm.nih.gov/protein/NP_008839.2]] belongs to a family of small GTPase binding protein called the RAS superfamily. This protein plays an important role in various cellular processes like cell motility, cellular growth, cell cycle and also cell-cell adhesion. Studies done by Grewal et.al., 2008 demonstrate that the invasion of the human embryonic tropoblast layer into the human endrometrial stromal cells requires mediation by the Rac-1 protein. Increased motility of the stromal cells increases the chances of implantation and an increased expression of Rac-1 activation corresponds with increase in motility. Rac-1 also works by down-regulating RhoA protein which is also important to promote embryo invasion. Since, successful implantation is imperative for pregnancy and fertility the role of Rac-1 is somewhat central to the process of implantation.

<pubmed> 18838676 </pubmed>

===Lab 3===

'''Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.'''

Gestational age is defined as the time period between conception and birth. It helps the clinicians determine how far along a women is in her pregnancy and is taken from the first day of the women's last menstural cycle (LMC). This is measured in weeks with a normal pregnancy lasting between 38-42 weeks. [[http://www.nlm.nih.gov/medlineplus/ency/article/002367.htm|Medline Plus - Gestational Age]]

Post fertilization age on the other hand is the time lapsed after the sperm enters the oocyte and cell division begins.

Gestational age is used as opposed to post fertilization age as it is easy to determine when the woman had her last menstrual cycle whereas the exact day/time of fertilization is hard to determine. Gestational age is easy to determine both before and after birth. While the foetus is growing it's size of the head, thigh bone and abdomen can be used to establish the gestational age. After the birth the length, size of the head, weight and other vital signs can be used to determine gestational age. Babies born before 37 weeks are said to be premature whereas after 42 weeks are post mature.

Clinically the infant's medical history and medical plan is determined based on the gestational age.

'''Identify using histological descriptions at least 3 different types of tissues formed from somites.'''

Histologically somite differentiate into dermis, cartilage and muscle.

The ventral medial portion of the somite becomes the sclerotome via Sonic hedgehog signalling mechanism. Transcription factor Pax 1 then converts the sclerotome into '''cartilage''' tissue imperative for the functioning of the vertebrae.

The dorsal portion of periaxial mesoderm is the dermatome which in response to factor neurotropin 3 changes into the '''dermis'''.

The medial portion of the somite expresses Wnt1 and Wnt3 factors that converts the myotome into expressing '''muscle''' related genes. Similarly Wnt proteins and bone morphogenetic protein 4 (BMP4) cause the expression of '''muscle''' related genes in the lateral portion of the somite.

[http://www.ncbi.nlm.nih.gov/books/NBK10085/|Developmental Biology. 6th edition. Gilbert SF. Sunderland (MA): Sinauer Associates; 2000. Paraxial Mesoderm: The Somites and Their Derivatives]

===Lab 4===

'''Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.'''

'''Chronic Villus Biopsy (CVB)''' or placental biopsy which involves use of a catheter through the cervix or transabdominal needle into the uterus in order to obtain placental tissue. Since the placenta is derived from the cells of the embryo it contains the genetic material of the foetus which can used for chromosomal analysis. The test is performed within 10-12 weeks of pregnancy and can be used to identify a range of genetic mutations (although not all) like Down's syndrome and Turner syndrome.

'''Amniocentesis''' is another invasive technique in which a needle is used to obtain a sample of the amniotic fluid via passing it through the mother's abdomen. It is normally performed between 14 to 20 weeks of gestation and is also used to account for any genetic abnormalities. The amniotic cells can be examined either by fluorescent techniques or by culturing them further. Along with chromosomal anomalies this procedure can also be used to diagnose for congenital metabolic diseases, neural tube defects, hereditary related genetic diseases like cystic fibrosis etc.

'''References'''

[http://www.genetics.edu.au/Information/Genetics-Fact-Sheets/PrenatalTestingCVSandAmniocentesisFS17c|PRENATAL TESTING – CVS AND AMNIOCENTESIS]

[http://www.embryology.ch/anglais/jfetalperiod/diagno04.html|Embryogenesis Prenatal diagnosis]

[http://library.med.utah.edu/WebPath/TUTORIAL/PRENATAL/PRENATAL.html|Prenatal Diagnosis]

<pubmed> 16533654 </pubmed>

'''Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''

<pubmed> 19156219 </pubmed>

Type 1 diabetes is a form of autoimmune disease involving destruction of beta cells of the pancreas which produce insulin that helps in maintaining glucose homoeostasis in the body. Deficiency of insulin causes an elevation in glucose levels of blood and urine. Normal treatment of insulin involves insulin injections which is administered daily to the patient. Although the treatment helps to replace the lost insulin it does not solve the autoimmunity problem. Studies done by Zhao et.al., 2009 indicate that using human cord blood stem cells in non obese diabetic mice helps to fight hyperglycaemia and helps restore original architect of the islets of langerhans by causing beta cell regeneration, increase in mass of beta cells and production of insulin.

By using immunostaining techniques showed that the diabetic rats that were untreated had around 80% of their beta cells destroyed whereas the diabetic rats that were treated with cord blood stem cells had a high proliferation rate of beta cells hence proving to be promising therapeutic agent to treat type 1 diabetes. Human cord stem cells can prove to be a viable treatment for type 1 diabetes as it does not involve any immune problems nor does it attract any ethical controversies. There is also a large resource available for cord blood worldwide.

===Lab 5 ===

Finish survey!

===Lab 6===

Working on group project

===Lab 7===

'''Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?'''

Satellite cells are a small population of quiescent muscle stem cells that reside in the skeletal muscle.

<pubmed>12757751</pubmed>

Short bursts of resistive activity or physical injury that causes chronic stress to the muscle can induce a hypertrophic response and recruitment of satellite cells. Since the integrity of satellite cells is maintained by the intactness of basal lamina any interruption during muscle trauma causes the cells might proliferate the adjacent myofibres. The cells can also travel via chemotaxis to the site of injury. After injury macrophages are recruited to the site as a result of immune response. These macrophages release a number of cytokines essential for recruitment, proliferation and differentiation of the satellite cells.

<pubmed>11457764</pubmed>

'''In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?'''

Long-term injury of the spinal cord damages the innervating motor nerve thus removing the connection between the nerve and the muscle thus depriving the muscle of various neurotropic factors. Over long term, atrophy develops as a result of disuse of the muscle causing degeneration of the myofibril and decrease in the number of satellite cells. Studies have found a decrease in the percentage of satellite cells to as low as 1% following an 18 month old nerve injury. Neurotropic factors are important for providing the growth factors for maintenance of the satellite cell population and denervation negatively impacts its function. After a period of prolonged denervation even if the nerve sprouts back the muscle cannot regain its lost function due to decrease in the reserve pool of satellite cells.

<pubmed> 9214552</pubmed>

===Lab 8===

'''Critical analysis of group projects'''

'''Group 1 - Vision'''

- the opening is very catchy with the diagram

- good brief introduction although it might help to give a brief description of the different parts.

- Since you have no other tables maybe put the history section in the table so it breaks up the text.

- It might be better to make the images a little bigger so we can see the labels. Also with the images for ‘formation of primary optic vesicles’ you might want to fix the way it’s laid out on the page --- may be put it in a table with a description of what each labelled part contributes to. Also there is no description bellow the pictures either. All the pictures in the development area looks very clustered so break it up with text.

-Large section of the optic nerve development ad retina development seems to have no references. But a lot of good detail is present which shows that you have researched. Although try to use articles rather than books.

- The student drawn images have tiny labels so fix that up maybe and also add copyright information.

- Fig 4 and 5’s formatting should be fixed so they are either side to side or broken up by text. Same goes with fig 6 and 7 – needs copyright info.

- In the current research section a detail of what the research is about and how it is helpful can be given.

- Try using less websites and more journal articles.

- Sections of ciliary body, iris and lens development could use some more detail. The section on iris has the development time in months…it will be beneficial if you kept it in weeks to be consistent with the rest of the parts. The section on lens, aqueous chamber and cornea doesn’t have any development time associated with it which might be useful too.

- I’m aware that you cant do abnormal section in detail but you can still mention some abnormalities in a section without going into heavy detail.

Overall it is a good page but formatting of the pictures and their placement has to be fixed. Some more text should be added to the development section of iris, lens, eyelids etc.

'''Group 2 - Somatosensory'''

- The introduction is small yet detailed --- I like how its an overview of the development. You do need to fix up the references though.

- You have in the intro section “the following picture….” But there is no picture there….if the picture is further ahead maybe write Fig 1 shows….and also label the picture.

- History section needs a bit work on – you should start with the earliest data and proceed in a chronological order so everyone can see the advancement in development of somatosensory organs.

- In the section of “Development of the primary somatosensory cortex” you have mentioned that there are intrinsic and extrinsic mechanisms --- you should mention what those signalling mechanisms are. Also if you are using the one ref for the whole paragraph do not put the ref after each line. Just put it in the end. Also it would be good to give the origin of the neurons like ecto, endo or meso.
- Its good how your description is divided into stages – it might help to give the weeks as well.

- For the touch section you have a lot of detail on what the receptors are which is fine but there is nothing about their development (which is what the project is about). The same thing is noted with “Pain” section – there is nothing on development. I’m sure you can put some genes or signalling molecules that are important for differentiation of cells into the different receptors.

At the moment your project is focused on what the different somatosensory receptors do but very little detail on how they develop, which is what you need to focus on.
More pictures are needed to break up the text.

'''Group 3 - Olfaction'''

- The introduction of taste is very descriptive and encapsulates the anatomy, physiology and cell biology. Although it is very detailed it doesn’t indicate that the project is about development.

- There is a lot of detail about the taste neural pathway and cortical areas which I’m not sure is relevant to olfactory development unless you mention how they develop as well.

- Figure 2 and 3 do not have any copyright information associated so remember to add those.

- The development section is very nicely put together and hopefully you will add images further down the line. I’ve noticed that in week 8 of development you have the same ref after each line…I’m sure you can just put it at the end of the paragraph as it is same for each line. Same goes for week 14 and 15. Also since you have 2 references for the entire section --- you might want to look at other articles as well.

- Some things that I missed in the section were patterning molecules and genes. Also any signalling mechanisms that control differentiation.

- The history section is exceptionally done with the use of tables, description and references.

- I thoroughly enjoyed your abnormality section. The images are nicely done as well. Although you have described many genes and molecules which are not specified in the normal development portion so the reader don’t understand their roles. Maybe address this in your normal development section.

- The current development section is also very nicely put together but again things like Shh and WNT should be in development section.

Overall very nicely put together and great balance of pictures and text. Although this is a development topic so the major emphasis should be on development of the organ --- Normal development is good but there is too much content in that section that can be left out.

'''Group 4 - Olfaction'''

- The introduction is very good and brief --- although it does not tell the reader that it is about development of olfactory sense.

- The history section is immaculately done --- You have used a couple different sources and gone into enough detail about each historic background which tells me that you have thoroughly research this part.

- The development section is also very nicely done --- I like the layout of this section. Also the sentences are very clear and structure is easy to follow. There is a large section in week 6 which does not have any reference so you might want to fix that up. Same goes for week 7 abd week 8.

- When you start talking about anosmia it just abruptly follows normal function so you might want to add the heading “abnormal development”. It might even be a good idea to put normal function before normal development to put things in perspective.

- In Kallmann’s syndrome although it was very interesting to read, it is very heavy on genes which you have not addressed in the normal section portion. I do realise for some of them you have put a description as to what they do in normal development but see if you can integrate it with normal development too.

- It is also good to see that you have a diagnosis section and a treatment section too. It was very informative.

- Current research is well put together

Overall your project is looking pretty good….Just some minor formatting issues. The text is a little on the heavy side some pictures especially in the development section will be good.

'''Group 5 - Abnormal Vision'''

- A very good start to the page with the introduction. It gives an overview of the page and is very nicely done --- an image in the beginning will make it more effective. Right now the starting is very text heavy so an image will not just tone it down but will have a more profound impact.

- Normal eye development is good too but just to make the text look not so heavy you can consider putting it in a table like a brief summary.

- Traditionally research timeline should go on the top of the page but I don’t think it’s a big issue. Again you should consider tabulating it so it looks not so text heavy.

- I like how you talk about each part of the eye and different genes. You have a range of articles which also seems great and shows how much effort you have put in.

- Research section is not so extensive so far so you might want to work on that.

At the moment the organisation of the page is not great and it is very text heavy. Even though there are many images on the page it still looks very text heavy. Adding tables might help breaking that up and also add make the page look bright.

===Lab 9===

'''Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

Study performed by McDonald and colleagues was aimed at establishing the role of Sox9 gene during human foetal pancreatic development as it had earlier shown to play an important role in the development of mice pancreas<ref><pubmed>17267606</pubmed></ref>. The pathological hallmark of diabetes is the reduction in the number of insulin producing beta cells and the aim of many stem cell therapy is to replace these lost cells. However in order for the progenitor cell to correctly differentiate and proliferate into beta cells correct signalling mechanisms are essential. By immunehistochemistry studies and western blot analysis it was confirmed that Sox9 is expressed in human foetal pancreas as early as week 8 and is highly expressed till week 20 and then rapidly declines. The study also confirmed that knockdown of Sox9 gene significantly lowers the number of cells that express beta-cell markers thereby indictaing the importance of Sox9 in development of human pancreas.

<pubmed>21983268</pubmed>

<references/>

'''Identify the embryonic layers and tissues that contribute to the developing teeth.'''

User:Z3333794

2012-10-02T11:42:49Z

Z3333794: /* Lab 9 */

==Lab Attendance==
'''Lab 1''' --[[User:Z3333794|Z3333794]] 10:59, 25 July 2012 (EST)

'''Lab 2''' --[[User:Z3333794|Z3333794]] 10:02, 1 August 2012 (EST)

'''Lab 3''' --[[User:Z3333794|Z3333794]] 10:10, 8 August 2012 (EST)

'''Lab 4''' --[[User:Z3333794|Z3333794]] 10:04, 15 August 2012 (EST)

'''Lab 5''' --[[User:Z3333794|Z3333794]] 09:49, 22 August 2012 (EST)

'''Lab 6''' --[[User:Z3333794|Z3333794]] 10:07, 29 August 2012 (EST)

'''Lab 7''' --[[User:Z3333794|Z3333794]] 10:07, 12 September 2012 (EST)

'''Lab 8''' --[[User:Z3333794|Z3333794]] 10:04, 19 September 2012 (EST)

'''Lab 9''' --[[User:Z3333794|Z3333794]] 10:01, 26 September 2012 (EST)

==Lab Exercises==

===Lab 1===

'''Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.'''

The roots of InVitro Fertilization (IVF) and Embryo Transfer (ET) dates back to the early 1890s where Walter Heape a dedicated professor and physician at the University of Cambridge in England whereby he reported the first case of embryo transplant in rabbits. He then went on to do more research in the field of reproduction on a variety of animal species. [http://www.ivf-worldwide.com/ivf-history.html IVF history]

IVF worldwide also articulates that the first in vitro fertilization of human oocytes was carried out in 1965 in John Hopkins Hospital, USA by Edwards and Jones and the first IVF pregnancy occurred in 1973 in the Melbourne, Australia by researchers Wood and Leeton. The pregnancy led to a miscarriage and the first IVF baby was born in England on 25th July 1978, 5 years later. [http://www.ivf-worldwide.com/ivf-history.html IVF history]

The 2010 Nobel prize in Physiology and Medicine was awarded to Robert G. Edwards for development of in vitro Fertilization. His contribution to embryology made a worldwide impact as it became a viable way to overcome infertility. [[http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/|Link Nobel Prize Winner 2010]]

'''Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).'''

In Vitro Fertilization technology has not only impacted humans as a way to overcome infertility but has majot implications for the animal society as well. It is used in breeding practices throughout the world to breed the best quality animals. To make sure the treatment is cost effective it is imperative that the process of IVF leads to a successful pregnancy and as a result birth. Research carried by Jimenez et.al., 2011 focuses at investigating the link between thickness of zona pellucida fertilization, embryo implantation and birth. By using video chromatography their team successfully concluded that the thickness of zona pelucida greatly impacted the fertilization process and transplantation but did not significantly impact in birth.

<pubmed> 22607772 </pubmed>

===Lab 2===

====Adding an Image with the class====

[[File:GnRH receptors (GnRHRs) and spatial expression patterns of gnrhr genes.png|500px]]

====Online Lab Questions====

'''Upload an image from a journal source relating to fertilization or the first 2 weeks of development.'''

[[File:Expression of CD82 in human placental villi and cell lines.JPG]]

'''Identify a protein associated with the implantation process, including a brief description of the protein's role.'''

The Rac-1 protein [[http://www.ncbi.nlm.nih.gov/protein/NP_008839.2]] belongs to a family of small GTPase binding protein called the RAS superfamily. This protein plays an important role in various cellular processes like cell motility, cellular growth, cell cycle and also cell-cell adhesion. Studies done by Grewal et.al., 2008 demonstrate that the invasion of the human embryonic tropoblast layer into the human endrometrial stromal cells requires mediation by the Rac-1 protein. Increased motility of the stromal cells increases the chances of implantation and an increased expression of Rac-1 activation corresponds with increase in motility. Rac-1 also works by down-regulating RhoA protein which is also important to promote embryo invasion. Since, successful implantation is imperative for pregnancy and fertility the role of Rac-1 is somewhat central to the process of implantation.

<pubmed> 18838676 </pubmed>

===Lab 3===

'''Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.'''

Gestational age is defined as the time period between conception and birth. It helps the clinicians determine how far along a women is in her pregnancy and is taken from the first day of the women's last menstural cycle (LMC). This is measured in weeks with a normal pregnancy lasting between 38-42 weeks. [[http://www.nlm.nih.gov/medlineplus/ency/article/002367.htm|Medline Plus - Gestational Age]]

Post fertilization age on the other hand is the time lapsed after the sperm enters the oocyte and cell division begins.

Gestational age is used as opposed to post fertilization age as it is easy to determine when the woman had her last menstrual cycle whereas the exact day/time of fertilization is hard to determine. Gestational age is easy to determine both before and after birth. While the foetus is growing it's size of the head, thigh bone and abdomen can be used to establish the gestational age. After the birth the length, size of the head, weight and other vital signs can be used to determine gestational age. Babies born before 37 weeks are said to be premature whereas after 42 weeks are post mature.

Clinically the infant's medical history and medical plan is determined based on the gestational age.

'''Identify using histological descriptions at least 3 different types of tissues formed from somites.'''

Histologically somite differentiate into dermis, cartilage and muscle.

The ventral medial portion of the somite becomes the sclerotome via Sonic hedgehog signalling mechanism. Transcription factor Pax 1 then converts the sclerotome into '''cartilage''' tissue imperative for the functioning of the vertebrae.

The dorsal portion of periaxial mesoderm is the dermatome which in response to factor neurotropin 3 changes into the '''dermis'''.

The medial portion of the somite expresses Wnt1 and Wnt3 factors that converts the myotome into expressing '''muscle''' related genes. Similarly Wnt proteins and bone morphogenetic protein 4 (BMP4) cause the expression of '''muscle''' related genes in the lateral portion of the somite.

[http://www.ncbi.nlm.nih.gov/books/NBK10085/|Developmental Biology. 6th edition. Gilbert SF. Sunderland (MA): Sinauer Associates; 2000. Paraxial Mesoderm: The Somites and Their Derivatives]

===Lab 4===

'''Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.'''

'''Chronic Villus Biopsy (CVB)''' or placental biopsy which involves use of a catheter through the cervix or transabdominal needle into the uterus in order to obtain placental tissue. Since the placenta is derived from the cells of the embryo it contains the genetic material of the foetus which can used for chromosomal analysis. The test is performed within 10-12 weeks of pregnancy and can be used to identify a range of genetic mutations (although not all) like Down's syndrome and Turner syndrome.

'''Amniocentesis''' is another invasive technique in which a needle is used to obtain a sample of the amniotic fluid via passing it through the mother's abdomen. It is normally performed between 14 to 20 weeks of gestation and is also used to account for any genetic abnormalities. The amniotic cells can be examined either by fluorescent techniques or by culturing them further. Along with chromosomal anomalies this procedure can also be used to diagnose for congenital metabolic diseases, neural tube defects, hereditary related genetic diseases like cystic fibrosis etc.

'''References'''

[http://www.genetics.edu.au/Information/Genetics-Fact-Sheets/PrenatalTestingCVSandAmniocentesisFS17c|PRENATAL TESTING – CVS AND AMNIOCENTESIS]

[http://www.embryology.ch/anglais/jfetalperiod/diagno04.html|Embryogenesis Prenatal diagnosis]

[http://library.med.utah.edu/WebPath/TUTORIAL/PRENATAL/PRENATAL.html|Prenatal Diagnosis]

<pubmed> 16533654 </pubmed>

'''Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''

<pubmed> 19156219 </pubmed>

Type 1 diabetes is a form of autoimmune disease involving destruction of beta cells of the pancreas which produce insulin that helps in maintaining glucose homoeostasis in the body. Deficiency of insulin causes an elevation in glucose levels of blood and urine. Normal treatment of insulin involves insulin injections which is administered daily to the patient. Although the treatment helps to replace the lost insulin it does not solve the autoimmunity problem. Studies done by Zhao et.al., 2009 indicate that using human cord blood stem cells in non obese diabetic mice helps to fight hyperglycaemia and helps restore original architect of the islets of langerhans by causing beta cell regeneration, increase in mass of beta cells and production of insulin.

By using immunostaining techniques showed that the diabetic rats that were untreated had around 80% of their beta cells destroyed whereas the diabetic rats that were treated with cord blood stem cells had a high proliferation rate of beta cells hence proving to be promising therapeutic agent to treat type 1 diabetes. Human cord stem cells can prove to be a viable treatment for type 1 diabetes as it does not involve any immune problems nor does it attract any ethical controversies. There is also a large resource available for cord blood worldwide.

===Lab 5 ===

Finish survey!

===Lab 6===

Working on group project

===Lab 7===

'''Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?'''

Satellite cells are a small population of quiescent muscle stem cells that reside in the skeletal muscle.

<pubmed>12757751</pubmed>

Short bursts of resistive activity or physical injury that causes chronic stress to the muscle can induce a hypertrophic response and recruitment of satellite cells. Since the integrity of satellite cells is maintained by the intactness of basal lamina any interruption during muscle trauma causes the cells might proliferate the adjacent myofibres. The cells can also travel via chemotaxis to the site of injury. After injury macrophages are recruited to the site as a result of immune response. These macrophages release a number of cytokines essential for recruitment, proliferation and differentiation of the satellite cells.

<pubmed>11457764</pubmed>

'''In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?'''

Long-term injury of the spinal cord damages the innervating motor nerve thus removing the connection between the nerve and the muscle thus depriving the muscle of various neurotropic factors. Over long term, atrophy develops as a result of disuse of the muscle causing degeneration of the myofibril and decrease in the number of satellite cells. Studies have found a decrease in the percentage of satellite cells to as low as 1% following an 18 month old nerve injury. Neurotropic factors are important for providing the growth factors for maintenance of the satellite cell population and denervation negatively impacts its function. After a period of prolonged denervation even if the nerve sprouts back the muscle cannot regain its lost function due to decrease in the reserve pool of satellite cells.

<pubmed> 9214552</pubmed>

===Lab 8===

'''Critical analysis of group projects'''

'''Group 1 - Vision'''

- the opening is very catchy with the diagram

- good brief introduction although it might help to give a brief description of the different parts.

- Since you have no other tables maybe put the history section in the table so it breaks up the text.

- It might be better to make the images a little bigger so we can see the labels. Also with the images for ‘formation of primary optic vesicles’ you might want to fix the way it’s laid out on the page --- may be put it in a table with a description of what each labelled part contributes to. Also there is no description bellow the pictures either. All the pictures in the development area looks very clustered so break it up with text.

-Large section of the optic nerve development ad retina development seems to have no references. But a lot of good detail is present which shows that you have researched. Although try to use articles rather than books.

- The student drawn images have tiny labels so fix that up maybe and also add copyright information.

- Fig 4 and 5’s formatting should be fixed so they are either side to side or broken up by text. Same goes with fig 6 and 7 – needs copyright info.

- In the current research section a detail of what the research is about and how it is helpful can be given.

- Try using less websites and more journal articles.

- Sections of ciliary body, iris and lens development could use some more detail. The section on iris has the development time in months…it will be beneficial if you kept it in weeks to be consistent with the rest of the parts. The section on lens, aqueous chamber and cornea doesn’t have any development time associated with it which might be useful too.

- I’m aware that you cant do abnormal section in detail but you can still mention some abnormalities in a section without going into heavy detail.

Overall it is a good page but formatting of the pictures and their placement has to be fixed. Some more text should be added to the development section of iris, lens, eyelids etc.

'''Group 2 - Somatosensory'''

- The introduction is small yet detailed --- I like how its an overview of the development. You do need to fix up the references though.

- You have in the intro section “the following picture….” But there is no picture there….if the picture is further ahead maybe write Fig 1 shows….and also label the picture.

- History section needs a bit work on – you should start with the earliest data and proceed in a chronological order so everyone can see the advancement in development of somatosensory organs.

- In the section of “Development of the primary somatosensory cortex” you have mentioned that there are intrinsic and extrinsic mechanisms --- you should mention what those signalling mechanisms are. Also if you are using the one ref for the whole paragraph do not put the ref after each line. Just put it in the end. Also it would be good to give the origin of the neurons like ecto, endo or meso.
- Its good how your description is divided into stages – it might help to give the weeks as well.

- For the touch section you have a lot of detail on what the receptors are which is fine but there is nothing about their development (which is what the project is about). The same thing is noted with “Pain” section – there is nothing on development. I’m sure you can put some genes or signalling molecules that are important for differentiation of cells into the different receptors.

At the moment your project is focused on what the different somatosensory receptors do but very little detail on how they develop, which is what you need to focus on.
More pictures are needed to break up the text.

'''Group 3 - Olfaction'''

- The introduction of taste is very descriptive and encapsulates the anatomy, physiology and cell biology. Although it is very detailed it doesn’t indicate that the project is about development.

- There is a lot of detail about the taste neural pathway and cortical areas which I’m not sure is relevant to olfactory development unless you mention how they develop as well.

- Figure 2 and 3 do not have any copyright information associated so remember to add those.

- The development section is very nicely put together and hopefully you will add images further down the line. I’ve noticed that in week 8 of development you have the same ref after each line…I’m sure you can just put it at the end of the paragraph as it is same for each line. Same goes for week 14 and 15. Also since you have 2 references for the entire section --- you might want to look at other articles as well.

- Some things that I missed in the section were patterning molecules and genes. Also any signalling mechanisms that control differentiation.

- The history section is exceptionally done with the use of tables, description and references.

- I thoroughly enjoyed your abnormality section. The images are nicely done as well. Although you have described many genes and molecules which are not specified in the normal development portion so the reader don’t understand their roles. Maybe address this in your normal development section.

- The current development section is also very nicely put together but again things like Shh and WNT should be in development section.

Overall very nicely put together and great balance of pictures and text. Although this is a development topic so the major emphasis should be on development of the organ --- Normal development is good but there is too much content in that section that can be left out.

'''Group 4 - Olfaction'''

- The introduction is very good and brief --- although it does not tell the reader that it is about development of olfactory sense.

- The history section is immaculately done --- You have used a couple different sources and gone into enough detail about each historic background which tells me that you have thoroughly research this part.

- The development section is also very nicely done --- I like the layout of this section. Also the sentences are very clear and structure is easy to follow. There is a large section in week 6 which does not have any reference so you might want to fix that up. Same goes for week 7 abd week 8.

- When you start talking about anosmia it just abruptly follows normal function so you might want to add the heading “abnormal development”. It might even be a good idea to put normal function before normal development to put things in perspective.

- In Kallmann’s syndrome although it was very interesting to read, it is very heavy on genes which you have not addressed in the normal section portion. I do realise for some of them you have put a description as to what they do in normal development but see if you can integrate it with normal development too.

- It is also good to see that you have a diagnosis section and a treatment section too. It was very informative.

- Current research is well put together

Overall your project is looking pretty good….Just some minor formatting issues. The text is a little on the heavy side some pictures especially in the development section will be good.

'''Group 5 - Abnormal Vision'''

- A very good start to the page with the introduction. It gives an overview of the page and is very nicely done --- an image in the beginning will make it more effective. Right now the starting is very text heavy so an image will not just tone it down but will have a more profound impact.

- Normal eye development is good too but just to make the text look not so heavy you can consider putting it in a table like a brief summary.

- Traditionally research timeline should go on the top of the page but I don’t think it’s a big issue. Again you should consider tabulating it so it looks not so text heavy.

- I like how you talk about each part of the eye and different genes. You have a range of articles which also seems great and shows how much effort you have put in.

- Research section is not so extensive so far so you might want to work on that.

At the moment the organisation of the page is not great and it is very text heavy. Even though there are many images on the page it still looks very text heavy. Adding tables might help breaking that up and also add make the page look bright.

===Lab 9===

'''Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

Study performed by McDonald and colleagues was aimed at establishing the role of Sox9 gene during human foetal pancreatic development as it had earlier shown to play an important role in the development of mice pancreas<ref><pubmed>17267606</pubmed></ref>. The pathological hallmark of diabetes is the reduction in the number of insulin producing beta cells and the aim of many stem cell therapy is to replace these lost cells. However in order for the progenitor cell to correctly differentiate and proliferate into beta cells correct signalling mechanisms are essential. By immunehistochemistry studies and western blot analysis it was confirmed that Sox9 is expressed in human foetal pancreas as early as week 8 and is highly expressed till week 20 and then rapidly declines. The study also confirmed that knockdown of Sox9 gene significantly lowers the number of cells that express beta-cell markers thereby indictaing the importance of Sox9 in development of human pancreas.

<pubmed>21983268</pubmed>

</references>

'''Identify the embryonic layers and tissues that contribute to the developing teeth.'''

User:Z3333794

2012-10-02T11:36:54Z

Z3333794: /* Lab 9 */

==Lab Attendance==
'''Lab 1''' --[[User:Z3333794|Z3333794]] 10:59, 25 July 2012 (EST)

'''Lab 2''' --[[User:Z3333794|Z3333794]] 10:02, 1 August 2012 (EST)

'''Lab 3''' --[[User:Z3333794|Z3333794]] 10:10, 8 August 2012 (EST)

'''Lab 4''' --[[User:Z3333794|Z3333794]] 10:04, 15 August 2012 (EST)

'''Lab 5''' --[[User:Z3333794|Z3333794]] 09:49, 22 August 2012 (EST)

'''Lab 6''' --[[User:Z3333794|Z3333794]] 10:07, 29 August 2012 (EST)

'''Lab 7''' --[[User:Z3333794|Z3333794]] 10:07, 12 September 2012 (EST)

'''Lab 8''' --[[User:Z3333794|Z3333794]] 10:04, 19 September 2012 (EST)

'''Lab 9''' --[[User:Z3333794|Z3333794]] 10:01, 26 September 2012 (EST)

==Lab Exercises==

===Lab 1===

'''Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.'''

The roots of InVitro Fertilization (IVF) and Embryo Transfer (ET) dates back to the early 1890s where Walter Heape a dedicated professor and physician at the University of Cambridge in England whereby he reported the first case of embryo transplant in rabbits. He then went on to do more research in the field of reproduction on a variety of animal species. [http://www.ivf-worldwide.com/ivf-history.html IVF history]

IVF worldwide also articulates that the first in vitro fertilization of human oocytes was carried out in 1965 in John Hopkins Hospital, USA by Edwards and Jones and the first IVF pregnancy occurred in 1973 in the Melbourne, Australia by researchers Wood and Leeton. The pregnancy led to a miscarriage and the first IVF baby was born in England on 25th July 1978, 5 years later. [http://www.ivf-worldwide.com/ivf-history.html IVF history]

The 2010 Nobel prize in Physiology and Medicine was awarded to Robert G. Edwards for development of in vitro Fertilization. His contribution to embryology made a worldwide impact as it became a viable way to overcome infertility. [[http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/|Link Nobel Prize Winner 2010]]

'''Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).'''

In Vitro Fertilization technology has not only impacted humans as a way to overcome infertility but has majot implications for the animal society as well. It is used in breeding practices throughout the world to breed the best quality animals. To make sure the treatment is cost effective it is imperative that the process of IVF leads to a successful pregnancy and as a result birth. Research carried by Jimenez et.al., 2011 focuses at investigating the link between thickness of zona pellucida fertilization, embryo implantation and birth. By using video chromatography their team successfully concluded that the thickness of zona pelucida greatly impacted the fertilization process and transplantation but did not significantly impact in birth.

<pubmed> 22607772 </pubmed>

===Lab 2===

====Adding an Image with the class====

[[File:GnRH receptors (GnRHRs) and spatial expression patterns of gnrhr genes.png|500px]]

====Online Lab Questions====

'''Upload an image from a journal source relating to fertilization or the first 2 weeks of development.'''

[[File:Expression of CD82 in human placental villi and cell lines.JPG]]

'''Identify a protein associated with the implantation process, including a brief description of the protein's role.'''

The Rac-1 protein [[http://www.ncbi.nlm.nih.gov/protein/NP_008839.2]] belongs to a family of small GTPase binding protein called the RAS superfamily. This protein plays an important role in various cellular processes like cell motility, cellular growth, cell cycle and also cell-cell adhesion. Studies done by Grewal et.al., 2008 demonstrate that the invasion of the human embryonic tropoblast layer into the human endrometrial stromal cells requires mediation by the Rac-1 protein. Increased motility of the stromal cells increases the chances of implantation and an increased expression of Rac-1 activation corresponds with increase in motility. Rac-1 also works by down-regulating RhoA protein which is also important to promote embryo invasion. Since, successful implantation is imperative for pregnancy and fertility the role of Rac-1 is somewhat central to the process of implantation.

<pubmed> 18838676 </pubmed>

===Lab 3===

'''Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.'''

Gestational age is defined as the time period between conception and birth. It helps the clinicians determine how far along a women is in her pregnancy and is taken from the first day of the women's last menstural cycle (LMC). This is measured in weeks with a normal pregnancy lasting between 38-42 weeks. [[http://www.nlm.nih.gov/medlineplus/ency/article/002367.htm|Medline Plus - Gestational Age]]

Post fertilization age on the other hand is the time lapsed after the sperm enters the oocyte and cell division begins.

Gestational age is used as opposed to post fertilization age as it is easy to determine when the woman had her last menstrual cycle whereas the exact day/time of fertilization is hard to determine. Gestational age is easy to determine both before and after birth. While the foetus is growing it's size of the head, thigh bone and abdomen can be used to establish the gestational age. After the birth the length, size of the head, weight and other vital signs can be used to determine gestational age. Babies born before 37 weeks are said to be premature whereas after 42 weeks are post mature.

Clinically the infant's medical history and medical plan is determined based on the gestational age.

'''Identify using histological descriptions at least 3 different types of tissues formed from somites.'''

Histologically somite differentiate into dermis, cartilage and muscle.

The ventral medial portion of the somite becomes the sclerotome via Sonic hedgehog signalling mechanism. Transcription factor Pax 1 then converts the sclerotome into '''cartilage''' tissue imperative for the functioning of the vertebrae.

The dorsal portion of periaxial mesoderm is the dermatome which in response to factor neurotropin 3 changes into the '''dermis'''.

The medial portion of the somite expresses Wnt1 and Wnt3 factors that converts the myotome into expressing '''muscle''' related genes. Similarly Wnt proteins and bone morphogenetic protein 4 (BMP4) cause the expression of '''muscle''' related genes in the lateral portion of the somite.

[http://www.ncbi.nlm.nih.gov/books/NBK10085/|Developmental Biology. 6th edition. Gilbert SF. Sunderland (MA): Sinauer Associates; 2000. Paraxial Mesoderm: The Somites and Their Derivatives]

===Lab 4===

'''Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.'''

'''Chronic Villus Biopsy (CVB)''' or placental biopsy which involves use of a catheter through the cervix or transabdominal needle into the uterus in order to obtain placental tissue. Since the placenta is derived from the cells of the embryo it contains the genetic material of the foetus which can used for chromosomal analysis. The test is performed within 10-12 weeks of pregnancy and can be used to identify a range of genetic mutations (although not all) like Down's syndrome and Turner syndrome.

'''Amniocentesis''' is another invasive technique in which a needle is used to obtain a sample of the amniotic fluid via passing it through the mother's abdomen. It is normally performed between 14 to 20 weeks of gestation and is also used to account for any genetic abnormalities. The amniotic cells can be examined either by fluorescent techniques or by culturing them further. Along with chromosomal anomalies this procedure can also be used to diagnose for congenital metabolic diseases, neural tube defects, hereditary related genetic diseases like cystic fibrosis etc.

'''References'''

[http://www.genetics.edu.au/Information/Genetics-Fact-Sheets/PrenatalTestingCVSandAmniocentesisFS17c|PRENATAL TESTING – CVS AND AMNIOCENTESIS]

[http://www.embryology.ch/anglais/jfetalperiod/diagno04.html|Embryogenesis Prenatal diagnosis]

[http://library.med.utah.edu/WebPath/TUTORIAL/PRENATAL/PRENATAL.html|Prenatal Diagnosis]

<pubmed> 16533654 </pubmed>

'''Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''

<pubmed> 19156219 </pubmed>

Type 1 diabetes is a form of autoimmune disease involving destruction of beta cells of the pancreas which produce insulin that helps in maintaining glucose homoeostasis in the body. Deficiency of insulin causes an elevation in glucose levels of blood and urine. Normal treatment of insulin involves insulin injections which is administered daily to the patient. Although the treatment helps to replace the lost insulin it does not solve the autoimmunity problem. Studies done by Zhao et.al., 2009 indicate that using human cord blood stem cells in non obese diabetic mice helps to fight hyperglycaemia and helps restore original architect of the islets of langerhans by causing beta cell regeneration, increase in mass of beta cells and production of insulin.

By using immunostaining techniques showed that the diabetic rats that were untreated had around 80% of their beta cells destroyed whereas the diabetic rats that were treated with cord blood stem cells had a high proliferation rate of beta cells hence proving to be promising therapeutic agent to treat type 1 diabetes. Human cord stem cells can prove to be a viable treatment for type 1 diabetes as it does not involve any immune problems nor does it attract any ethical controversies. There is also a large resource available for cord blood worldwide.

===Lab 5 ===

Finish survey!

===Lab 6===

Working on group project

===Lab 7===

'''Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?'''

Satellite cells are a small population of quiescent muscle stem cells that reside in the skeletal muscle.

<pubmed>12757751</pubmed>

Short bursts of resistive activity or physical injury that causes chronic stress to the muscle can induce a hypertrophic response and recruitment of satellite cells. Since the integrity of satellite cells is maintained by the intactness of basal lamina any interruption during muscle trauma causes the cells might proliferate the adjacent myofibres. The cells can also travel via chemotaxis to the site of injury. After injury macrophages are recruited to the site as a result of immune response. These macrophages release a number of cytokines essential for recruitment, proliferation and differentiation of the satellite cells.

<pubmed>11457764</pubmed>

'''In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?'''

Long-term injury of the spinal cord damages the innervating motor nerve thus removing the connection between the nerve and the muscle thus depriving the muscle of various neurotropic factors. Over long term, atrophy develops as a result of disuse of the muscle causing degeneration of the myofibril and decrease in the number of satellite cells. Studies have found a decrease in the percentage of satellite cells to as low as 1% following an 18 month old nerve injury. Neurotropic factors are important for providing the growth factors for maintenance of the satellite cell population and denervation negatively impacts its function. After a period of prolonged denervation even if the nerve sprouts back the muscle cannot regain its lost function due to decrease in the reserve pool of satellite cells.

<pubmed> 9214552</pubmed>

===Lab 8===

'''Critical analysis of group projects'''

'''Group 1 - Vision'''

- the opening is very catchy with the diagram

- good brief introduction although it might help to give a brief description of the different parts.

- Since you have no other tables maybe put the history section in the table so it breaks up the text.

- It might be better to make the images a little bigger so we can see the labels. Also with the images for ‘formation of primary optic vesicles’ you might want to fix the way it’s laid out on the page --- may be put it in a table with a description of what each labelled part contributes to. Also there is no description bellow the pictures either. All the pictures in the development area looks very clustered so break it up with text.

-Large section of the optic nerve development ad retina development seems to have no references. But a lot of good detail is present which shows that you have researched. Although try to use articles rather than books.

- The student drawn images have tiny labels so fix that up maybe and also add copyright information.

- Fig 4 and 5’s formatting should be fixed so they are either side to side or broken up by text. Same goes with fig 6 and 7 – needs copyright info.

- In the current research section a detail of what the research is about and how it is helpful can be given.

- Try using less websites and more journal articles.

- Sections of ciliary body, iris and lens development could use some more detail. The section on iris has the development time in months…it will be beneficial if you kept it in weeks to be consistent with the rest of the parts. The section on lens, aqueous chamber and cornea doesn’t have any development time associated with it which might be useful too.

- I’m aware that you cant do abnormal section in detail but you can still mention some abnormalities in a section without going into heavy detail.

Overall it is a good page but formatting of the pictures and their placement has to be fixed. Some more text should be added to the development section of iris, lens, eyelids etc.

'''Group 2 - Somatosensory'''

- The introduction is small yet detailed --- I like how its an overview of the development. You do need to fix up the references though.

- You have in the intro section “the following picture….” But there is no picture there….if the picture is further ahead maybe write Fig 1 shows….and also label the picture.

- History section needs a bit work on – you should start with the earliest data and proceed in a chronological order so everyone can see the advancement in development of somatosensory organs.

- In the section of “Development of the primary somatosensory cortex” you have mentioned that there are intrinsic and extrinsic mechanisms --- you should mention what those signalling mechanisms are. Also if you are using the one ref for the whole paragraph do not put the ref after each line. Just put it in the end. Also it would be good to give the origin of the neurons like ecto, endo or meso.
- Its good how your description is divided into stages – it might help to give the weeks as well.

- For the touch section you have a lot of detail on what the receptors are which is fine but there is nothing about their development (which is what the project is about). The same thing is noted with “Pain” section – there is nothing on development. I’m sure you can put some genes or signalling molecules that are important for differentiation of cells into the different receptors.

At the moment your project is focused on what the different somatosensory receptors do but very little detail on how they develop, which is what you need to focus on.
More pictures are needed to break up the text.

'''Group 3 - Olfaction'''

- The introduction of taste is very descriptive and encapsulates the anatomy, physiology and cell biology. Although it is very detailed it doesn’t indicate that the project is about development.

- There is a lot of detail about the taste neural pathway and cortical areas which I’m not sure is relevant to olfactory development unless you mention how they develop as well.

- Figure 2 and 3 do not have any copyright information associated so remember to add those.

- The development section is very nicely put together and hopefully you will add images further down the line. I’ve noticed that in week 8 of development you have the same ref after each line…I’m sure you can just put it at the end of the paragraph as it is same for each line. Same goes for week 14 and 15. Also since you have 2 references for the entire section --- you might want to look at other articles as well.

- Some things that I missed in the section were patterning molecules and genes. Also any signalling mechanisms that control differentiation.

- The history section is exceptionally done with the use of tables, description and references.

- I thoroughly enjoyed your abnormality section. The images are nicely done as well. Although you have described many genes and molecules which are not specified in the normal development portion so the reader don’t understand their roles. Maybe address this in your normal development section.

- The current development section is also very nicely put together but again things like Shh and WNT should be in development section.

Overall very nicely put together and great balance of pictures and text. Although this is a development topic so the major emphasis should be on development of the organ --- Normal development is good but there is too much content in that section that can be left out.

'''Group 4 - Olfaction'''

- The introduction is very good and brief --- although it does not tell the reader that it is about development of olfactory sense.

- The history section is immaculately done --- You have used a couple different sources and gone into enough detail about each historic background which tells me that you have thoroughly research this part.

- The development section is also very nicely done --- I like the layout of this section. Also the sentences are very clear and structure is easy to follow. There is a large section in week 6 which does not have any reference so you might want to fix that up. Same goes for week 7 abd week 8.

- When you start talking about anosmia it just abruptly follows normal function so you might want to add the heading “abnormal development”. It might even be a good idea to put normal function before normal development to put things in perspective.

- In Kallmann’s syndrome although it was very interesting to read, it is very heavy on genes which you have not addressed in the normal section portion. I do realise for some of them you have put a description as to what they do in normal development but see if you can integrate it with normal development too.

- It is also good to see that you have a diagnosis section and a treatment section too. It was very informative.

- Current research is well put together

Overall your project is looking pretty good….Just some minor formatting issues. The text is a little on the heavy side some pictures especially in the development section will be good.

'''Group 5 - Abnormal Vision'''

- A very good start to the page with the introduction. It gives an overview of the page and is very nicely done --- an image in the beginning will make it more effective. Right now the starting is very text heavy so an image will not just tone it down but will have a more profound impact.

- Normal eye development is good too but just to make the text look not so heavy you can consider putting it in a table like a brief summary.

- Traditionally research timeline should go on the top of the page but I don’t think it’s a big issue. Again you should consider tabulating it so it looks not so text heavy.

- I like how you talk about each part of the eye and different genes. You have a range of articles which also seems great and shows how much effort you have put in.

- Research section is not so extensive so far so you might want to work on that.

At the moment the organisation of the page is not great and it is very text heavy. Even though there are many images on the page it still looks very text heavy. Adding tables might help breaking that up and also add make the page look bright.

===Lab 9===

'''Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

Study performed by McDonald and colleagues was aimed at establishing the role of Sox9 gene during human foetal pancreatic development as it had earlier shown to play an important role in the development of mice pancreas. The pathological hallmark of diabetes is the reduction in the number of insulin producing beta cells and the aim of many stem cell therapy is to replace these lost cells. Howeve in order for the progenitor cell to correctly differentiate and proliferate into beta cells correct signalling mechanisms are essential. By immunehistochemistry studies and western blot analysis it was confirmed that Sox9 is expressed in human foetal pancreas as early as week 8 and is highly expressed till week 20 and then rapidly declines. The study also confirmed that knockdown of Sox9 gene significantly lowers the number of cells that express beta-cell markers thereby indictaing the importance of Sox9 in development of human pancreas.

<pubmed>21983268</pubmed>

'''Identify the embryonic layers and tissues that contribute to the developing teeth.'''

2012 Group Project 6

2012-10-02T05:45:18Z

Z3333794: /* Hearing Development */

[[File: z3333865.Ruby.jpeg | 450px| right]]
= Hearing Development=

==Introduction==

CAN YOU HEAR ME! – Hearing is one of the most important sense and an inherent part of human life. It widens our scope of life and allows us to work, relax, communicate, learn and form memories. The sense of hearing has evolved through the years in vertebrates is inherent for both hunting and surviving. The sound energy produced has be converted into an electrical signal for us to make sense of it. For successful transmission the correct development of the ear is of utmost important. Not only formation of the structures but also their correct assembly is imperative to normal ear functioning. In this project we will discuss the development of human ear from implantation to birth by shining light on the differentiation of cells and signalling mechanisms that lead to normal development. We will also talk about some abnormal processes and mutations which lead to various structural and functional diseases.

==History==

{| cellpadding=5 style="border:2px solid #08E8DE"
|- bgcolor= #00BFFF
|'''Date''' || '''Description'''
|- bgcolor=#87CEEB
|'''1536''' || The first clear distinction is made between the middle and inner ear. How to observe the middle ear ossicles is also explained. <ref><pubmed>4598483</pubmed></ref> <ref name="PMID6341584"><pubmed>6341584</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1438986/?page=6 Nicola Massa.]
|- bgcolor=#ADD8E6
| '''1543''' || ''De fabrica'' by Andreas Vesalius was published which identified and named the incus and the malleus. Also identified the tensor tympani and the anatomical position of the oval window to the round window <ref><pubmed>22581496</pubmed></ref>. [http://www.ncbi.nlm.nih.gov/pubmed/22581496 Andreas Vesalius]
|- bgcolor=#87CEEB
|''' 1561''' || ''Observationes anatomicae'' is published and describes the tympanic membrane. The stapes ossicle is also discovered and named. <ref><pubmed>22965774</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pubmed/22965774 Gabriele Falloppio]
|- bgcolor=#ADD8E6
| '''1563''' || In the book ''De Auditus Organis'', it was proposed that the tympanic membrane is connected to the nasopharynx. This tube was named after the writer of the book. He also completed the diescritpion of the tensor tymapani: <ref><pubmed>7029021</pubmed></ref>[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142106 Bartolomeo Eustachi]
|- bgcolor=#87CEEB
|'''17th Century'''|| The Metal ear was one of the first hearing aids created. It was placed over the ear to channel sound into the ear.
|- bgcolor=#ADD8E6
| '''1648''' ||Athanasius Kircher describes the ear trumpet: [http://www.ncbi.nlm.nih.gov/pubmed/10986798 Athanasius Kircher]
|- bgcolor=#87CEEB
|'''1683''' || The bony labyrinth is described in more detail. It is determined the spiral lamina has a bony and membranous part, and it divides the spiral duct into an upper and lower compartment. <ref name="PMID6341584"/>[http://www.sciencedirect.com/science/article/pii/S1286011510000172 Duverney.]
|- bgcolor=#ADD8E6
|'''1704'''|| The book ''De aure humana tractatus'' with information regarding the anatomy, physiology and pathology of the ear is published.<ref name="PMC1142106"><pubmed>PMC1142106</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142106/ Valsalva.]
|- bgcolor= #87CEEB
|'''1707'''|| It is proposed that the labyrinth contains fluid instead of air. <ref name="PMC1142106"/> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142106/ Valsalva.]
|- bgcolor=#ADD8E6
| '''1772'''|| Antonio Scarpa discovers the ear labyrinth <ref><pubmed>11314703</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pubmed/11314703 Scarpa.]
|- bgcolor= #87CEEB
|'''1789'''|| The membranous labyrinth is shown to consist of semicircular canals and the vestibular sacs. These form one system and are different to the periosteum. <ref><pubmed>11314703</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pubmed/11314703 Scarpa.]
|- bgcolor=#ADD8E6
| '''1831''' || It was discovered that the membranous labyrinth develops from a pit in the skin.It was also discovered that the spiral lamina is hollow. <ref><pubmed>1910378</pubmed></ref> [http://www.encyclopedia.com/doc/1G2-2830902099.html Huschke.]
|- bgcolor=#87CEEB
| '''1851''' || The cochlea is discovered in the inner ear, and parts of it, including the sensory epithelium, the spiral ganglion, the tectorial membrane, and the stria vascularis are described. [http://www.ncbi.nlm.nih.gov/pubmed/3517746 Alfonso Corti.]
|- bgcolor=#ADD8E6
|'''1898'''|| The first electric hearing aid, the Akouphone, was developed. A carbon transmitter allowed the hearing aid to be portable. [http://www.earhelp.co.uk/who-was-miller-reese-hutchinson.html Miller Reese Hutchison.]
|- bgcolor=#87CEEB
|'''1961'''|| Georg Von Békésy was awarded the Nobel Prize in Physiology or Medicine. He was awarded on this research on the sound waves at different frequencies on the nerve fibres. the research showed that the hair cells were activated along the cochlea correlated to the position of the cochlea. [http://www.ncbi.nlm.nih.gov/pubmed/14584991 Georg Von Békésy.]
|- bgcolor=#ADD8E6
|'''1978'''|| For the first time, a cochlear implant allowed a person to hear again. [http://www.abc.net.au/gnt/profiles/Transcripts/s1117832.htm Professor Graeme Clark.]
|- bgcolor=#87CEEB
| '''2012'''|| For the first time, human embryonic stem cells were used and proven to be effective in restoring hearing. See Current Research below and the [http://www.actiononhearingloss.org.uk/news-and-events/all-regions/press-releases/human-stem-cells-restore-hearing.aspx news article.]
|}

==Adult Ear: Overview of Anatomy and Physiology==

[[File:Anatomy_of_the_Ear.JPG|thumb|left|350px|Anatomy of the ear]]

In order for mammals to hear, sound energy in the air has to move the hair cells located inside the inner ears of mammals. The ear provides us with the suitable apparatus to convert the longitudinal sound waves into mechanical ones in order to move the hair cells located in the inner ear. The Pinna or the auricle is designed such that the sound waves coming in get directed into the external auditory meatus. The waves travel through the EAM hit the tympanic membrane or eardrum, which causes it to vibrate. The malleus, which is in contact with the tympanic membrane, moves which in turn moves the other ossicles. The ossicles namely malleus, incus and stapes provide solid medium for the waves to travel through and act as a lever increasing the amplitude of the sound wave 20 times.

[[File:Histology_of_Inner_Ear.png|thumb|right|300px|Histology of Inner Ear]]

The oval window marks the boundary between the middle and the inner ear, which constitutes of an outer bony labyrinth and an inner membranous labyrinth. The cochlea which is a coil resembling a snail’s shell houses the organ of Corti, the peripheral receptor for hearing. Histologically the cochlea is divided into 3 parts scala vestibule, scala media and the scala tympani divided by the vestibular and basilar membrane respectively.

The sound waves are transmitted from the stapes into the oval window. The vibrations cause movement of the perilymph fluid in the scala vestibuli into the scala media causing movement of basilar membrane and bending of the hair cells. The bending of the cells causes them to activate which sends signals down the vestibulocochlear nerve. The nerve impulses travel from this neve through the brainstem to the thalamus to the primary auditory cortex, which is located on the transverse temporal gyrus.

The basilar membrane has a tonotopic organisation and human ears can hear sounds ranging from 20-20000 Hz. Near the apex of the cochlea the basilar membrane is wide and loose whereas near the base is narrow and tight hence enabling us to hear different frequencies.

==Development==

The development of outer ear is attributed to the first pharyngeal arch. All the germ layer namely endoderm, mesoderm and ectoderm contribute to its formation. <ref><pubmed>8287791</pubmed></ref>

The pharyngeal arches arise as a series of bulges arising laterally from the embryo head around 3-4 weeks of human development. The arches have a consistent organisation of the endoderm, ectoderm and mesoderm. The ectoderm forms the outer surface of the arch with the core made up of mesoderm. Next to the mesoderm core on the opposite the ectoderm is the endoderm. All three layers contribute to the formation of outer, middle and inner ear structures hence contributing to hearing. In between the arches the ectoderm and endoderm come in contact with each other forming a continuous sheath on either side of the mesoderm, forming groves externally and arches internally. Inside the mesoderm core of each arch lies a specific cell population that goes onto develop into a nerve, cartilage and artery.

===Outer Ear===

'''Pinna'''

[[File:Devt_of_external_ear.JPG|thumb|400px|The image depicts the development of the pinna through the fetal development stages]]

Post development the anatomy of the external ear simply consists of the pinna or the auricle and external acoustic/auditory meatus. The auricle develops around the first and second pharyngeal arches as a series of auricular enlargements or hillocks around the 5th week of development. Gradually by the 6th week the hillocks grow in size and increase to six in number, three on the first arch and 3 on the second arch, the first of which starts at the bottom anterior side going in a clockwise direction. In the 7th week the hillocks enlarge further and each of the arches contributes to a specific part of the pinna. The first arch gives rise to the tragus, helix and cymba concha whereas arch 2 gives rise to concha, antihelix and antitragus. The differentiation starts around the neck region but as the mandible develops the pinna structures move more cranially. It is not until the 12th week that the fusion of these various parts occur and is completed by week 20th.

Various genetic markers and coordinated signalling mechanisms are required for normal development of the pinna. One of which is the EYA1 gene, which is imperative for formation of the pinna. Mice with a homologous Eya1 null gene either has malformed or absent ears and since Eya1 gene plays a role in the formation of cartilage, its absence doesn’t allow the ear mesenchyme to convert into ear cartilage. Another gene important for pinna cartilage formation is the Bmp5 gene that is expressed later in development, mutation in which causes malformation of the perichondrium and thus cartilage formation. Another gene important for early patterning of the pinna is the Hox2 gene, mutations in which leads to formation of a shapeless protuberance rather than a normal shaped pinna. Hox2 gene is expressed in the second pharyngeal arch and the malformations in the ear are contributed to the parts derived from the second pharyngeal arch like the antitragus, antihelix and concha.
<ref><pubmed>14674478</pubmed></ref> <ref><pubmed>17104502</pubmed></ref>

'''External Auditory Meatus'''

The External Auditory Meatus (EAM) is derived from ectoderm that forms the first pharyngeal groove situated between the 1st and the 2nd pharyngeal arches. At 8 weeks of gestation a c-shaped skeletal structure develops from ectoderm of the first pharyngeal cleft migrating and meeting the mesoderm of the first grove called the tympanic ring that controls and coordinates the invagination of the ectoderm. The tympanic ring is a transient embryological structure, which eventually gets integrated into the temporal bone and provides anchorage to the eardrum. Medial to the ring lays the endoderm of the first pharyngeal arch that contributes to the formation of the tympanic or middle ear cavity. At 12 weeks of gestation the tympanic ring begins to ossify in a sequential fashion via endomembranous ossification forming the bony part of the EAM. The ring starts to condense at the proximal end of the 1st pharyngeal arch, goes around the circumference of the cleft and invades the 2nd arch. Starting at the tip of the 1st pharyngeal cleft the ectodermal cells begin to proliferate filling the lumen of the meatus forming a meatal plug which medially extends in a disc like fashion during week 10. The proliferation follows the path of the tympanic ring with the mesoderm tissue between the ring and the meatus forming a fibrous layer. In week 13 of development the innermost part of the meatal plug makes a contact with malleus. This innermost part of the disc in week 15 splits leaving a thin endoderm layer behind which contributes to formation of the tympanic membrane. By the middle of 16th week the meatus although full in length is still narrow and curved and it is not until week 18 that it gets fully expanded and complete.

Since the correct development of EAM is heavily dependent on the tympanic ring, hence any mutation in the tympanic ring causes an abnormal growth of the EAM. Many genes are required to coordinate and control tympanic ring formation most prominent being the Gsc and Prx1 genes. Chimeric studies have revealed that tympanic ring in Gsc null mice fails to ossify whereas the ring whereas mice with null Prx1 gene have an over ossified tympanic ring. In both cases the meatus fails to form indicating a delicate balance between the expressions of both genes is required for proper ring development hence correct formation of EAM. Likewise for pinna formation Hox2 gene is also essential for differentiation of pharyngeal arch into the tympanic ring and the formation of EAM. <ref><pubmed>10976045</pubmed></ref> <ref><pubmed>14674478</pubmed></ref> <ref><pubmed>1441991</pubmed></ref>

===Middle Ear===

'''Tympanic Membrane'''

Tympanic membrane or the eardrum forms the boundary between the outer and middle ear and responsible for transmitting the soundwaves coming in from the EAM to the mechanical waves going into the ossicles. During 8th week of gestation the development of tympanic membrane begins when the first funnel shaped ectodermal cleft meets the endodermal pouch with the mesenchyme growing in-between. This mesenchyme eventually becomes thinner and forms the eardrum during week 12. The diameter of the membrane grows three fold between week 11 and 16 and the membrane fuses with the tympanic ring.

The 1st pharyngeal cleft (ectoderm) gives rise to the EAM and the tympanic membrane comes from the mesoderm from the 1s pharyngeal arch. The 1st pharyngeal pouch (endodermal in origin) proliferates to giving rise to the tubotympanic recess at 3rd gestational week. During week 7 the 2nd pharyngeal arch constricts the tympanic recess dividing it into a medial portion that form the Eustachian tube and a lateral portion that forms the tympanic cavity. <ref><pubmed> 17346562</pubmed></ref> <ref><pubmed> 10976045</pubmed></ref> <ref><pubmed> 2921547</pubmed></ref>

'''The Ossicles'''

The middle ear constitutes of the skeletal structures called ossicles, which amplify and transmit sound to the inner ear.

The middle ear consists of the middle ear cavity and it are housed the 3 ossicles – the malleus, incus and stapes from lateral to medial. The mesenchymal tissue or the neural crest cells from 1st and 2nd pharyngeal arch contributes to the formation of the ossicular chain.

Two main theories underlie the formation of the ossicles. First is the classical theory according to which the malleus and incus develops from the first pharyngeal arch whereas stapes develops from the 2nd pharyngeal arch. Another theory proposes that malleal head and body of incus comes from the first pharyngeal arch while the second arch gives rise to stapes, handle of malleus and long process of incus. <ref><pubmed>18803631</pubmed></ref>.

[[File:normal cochlea.png |thumb|150px|Wild-type inner ear showing normal morphology]]

===Inner Ear===

The entire inner ear, as well as the neurons which innervate the sensory organ, are derived from the otic placode.
The otic placode is a thickened portion of ectoderm located on the each side of the developing head of the embryo, next to the hindbrain. It is generally visible after gastrulation, once the first 5 to 10 pairs of somites have formed. Invagination occurs next, which creates the otocyst - a vesicle which will develop into the different components of the inner ear: the cochlea, the semicircular canals with cristae, the utricle, the saccule and the vestibulo-acoustic ganglion. <ref name="PMID17891709"><pubmed>17891709</pubmed></ref>[[File:z3333865.stages development inner ear.jpg|thumb|300px|Developmental milestones in mouse inner ear formation]]

====The Otic Placode====

'''Induction of the otic placode'''

Experiments with molecular markers have revealed that several steps are needed for induction of the otic placode.

We will briefly consider the three major steps:

'''1''' ''Pre-placodal domain''

The pre-placodal domain is a narrow strip of the ectoderm adjacent to the anterior neural plate after gastrulation. Different placodes arise from the pre-placodal domain. All the craniofacial sensory organs, including the ear, develop from these different placodes located at the periphery of the neural plate.

Various evidence indicates the existence of this pre-placodal region:

* Morphology indicates a thickened band of ectoderm around the anterior neural plate in some species, including mice and humans. As time progresses, this thickening will only be present at the locations where the different craniofacial placodes differentiate - including the otic placode.<ref><pubmed>15531360</pubmed></ref>

* Experiments have also shown that the placodes will only develop in the correct location, if rotation of the ectoderm along the anteroposterior axis takes place at the open neural plate stage. If rotation takes place at a later time, the placodes will form at incorrect places.<ref><pubmed>14100031</pubmed></ref>

* Gene expression has also indicated that particular genes are present in the pre-placodal domain. These genes belong to the Dlx, Six, Eya, Iro, BMP, Foxi and Msx families. Glavic et al. (2004) has shown that 'loss and gain of function of some of these genes resulted in the widening or reduction of the pre-placodal field'. Linked to this was also the domain of expression of some placode-specific genes; which either enlarged or diminished.<ref><pubmed>15242793</pubmed></ref>

'''2''' ''Pre-otic field''
[[File:z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared]]

Once the general placodal state has been established, the identity of each placode is induced by local signals. The optic placode is induced by various signals, including Pax8, Pax2, Fibroblast Growth Factors (FGFs), and many transciption factors.

In particular the FGFs are significant otic inducers. Signalling occurs from various rhombomeres from the hindbrain and the cranial paraxial mesoderm located beneath the area of the otic placode. For example, in mice FGF3 is expressed in rhombomeres
5 and 6, whereas FGF10 is expressed in the underlying mesoderm.<ref><pubmed>7789270</pubmed></ref> <ref name="PMID12810586"><pubmed>12810586</pubmed></ref> Mutations of FGF3 and FGF10 have been investigated. Results showed that mice with a mutation of either FGF3 or FGF10 developed an abnormal otic vesicle, and a combination of the two mutants resulted in failure to form an otic vesicle.<ref name="PMID12810586"/>

''--> picture''

'''3''' ''Otic placode/epidermis fate decision''

In the presence of FGF signalling, Wnt signalling can significantly influence the next step, which is the otic placode/epidermis fate decision. According to the review article by Ohyama ''et al''. (2007) ‘Cells receiving high levels of Wnt signalling differentiate as otic placode, while cells receiving little or no Wnt signalling differentiate as epidermis.’<ref name="PMID17891709"/>

The first evidence regarding the contribution of Wnt signalling came from experiments with the otic ectoderm of chicks.
* Data showed that specific marker genes, such as Pax2, were induced to a greater extend with FGF19 and Wnt8c present as compared to FGF19 alone <ref><pubmed>11110663</pubmed></ref>. Ladher ''et al''.(2000) hypothesised that FGF19 induced Wnt8c, and together they induced the otic gene markers.

Another possibility is the independent action of FGFs and Wnt signalling.
* Studies have shown that Wnt signalling onto Pax2+ cells results in differentiation of those cells into otic placode tissue. Pax2+ cells that were not exposed to Wnt signalling differentiate as epidermis <ref name="PMID16452098"><pubmed>16452098</pubmed></ref>.
* Wnt signalling also suppresses Foxi2, resulting in a Foxi2-negative area of particular size, which then allows for FGFs to induce otic genes <ref name="PMID16452098"/>. In this case, Wnt signalling determined the size of the otic placode, yet acted independently from FGF signalling.
* Phillips et al. (2004) studied the role of FGF and Wnt signalling; specifically looking at FGF3, FGF8 and Wnt8. Their data showed that Wnt8 is not absolutely necessary for otic induction, however it is required for timely initiation of the otic field. <ref><pubmed>14757644</pubmed></ref>

'''The neural domain'''
[[File:neural domain.jpg|thumb|200px|The expression of Sox2 and Sox3 during development of the ear]]
During the early stages of embryonic development, a neural competent domain is established. This domain will eventually give rise to neurons and hair cells. Various signalling pathways are required to initially create this domain and to maintain it later on. <ref name="PMID19247974"><pubmed>19247974</pubmed></ref>

* ''FGF and Sox''
FGF signalling and the Sox genes are essential for the establishment of the neural competent domain. An important aspect of Sox genes is that they have a state of self-renewal, as well as a state of neural commitment. <ref><pubmed>15863505</pubmed></ref>
As investigated by Rex et al. (1997) and Pevny and Placzek (2005), "SoxB1 genes (Sox1, Sox2, Sox3) have been linked directly to ectodermal cells that are competent to acquire neural fate, and the commitment of cells to a neural fate".<ref><pubmed>9215646</pubmed></ref> <ref><pubmed>15721738</pubmed></ref>

Before the otic placode becomes distinct, Sox3 is already expressed in a broad area around the location of the future otic placode. Later in it will only be found in the proneural region of the otic placode. Based on this, the review by Alsina et al. (2009) suggests that a neural fate acquisition occurs prior to otic placode formation.<ref name="PMID19247974"/> During the early stages of development of the otocyst, Sox2 and Sox3 are found in proliferating cells within the proneural region. Both are expressed when neurons are generated, however, Sox3 switches off and only Sox2 remains during further development of the ear. This suggests that the ongoing expression of Sox2 plays a role in sensory cell development, as explained in the review by Alsina et al (2009).<ref name="PMID19247974"/>

-We will look into this in further detail when describing the development of the elementary sensory unit of the ear-

* ''Notch signalling''
Notch signalling is required for several developmental processes, including the maintenance of the neural competent domain.

In the notch signalling pathway, notch is the receptor, with most of its ligands being transmembrane proteins. Signalling is therefore restricted to neighbouring cells. Research by Daudet and Lewis (2005) reveiled how notch signalling plays a role in inner ear development, including:

- Notch signalling mediates lateral inhibition and thereby controls the differentiation of hair cells and supporting cells - in particular in the vestibular regions <ref name="PMID15634704"><pubmed>15634704</pubmed></ref>

- An early phase of Notch activity promotes formation of prosensory patches <ref name="PMID15634704"/>

- Other signalling pathways are likely to cooperate with Notch to specify prosensory regions of the otocyst <ref name="PMID15634704"/>

====The Otocyst====
[[File:neural fate.jpg|thumb|200px|Recent model related to sensory fate.]]

'''Patterning of the otocyst'''

The otocyst, also known as the otic vesicle, is present once invagination of the otic placode has occurred. Regionalisation of the otocyst results in the topological organisation of the ear. The neural tube affects the patterning of the otocyst, and FGF, Wnt and Hh signalling pathways are also known to play a role.
FGF and Wnt rely on signals from the hindbrain. <ref><pubmed>17891710</pubmed></ref>

Prosensory patches emerge within the otocyst. These develop as a differentiate from the neural competent domain.<ref name="PMID21266409"><pubmed>21266409</pubmed></ref>

- haircells (sensory patch)

- neurons (neural competent domain)

As proposed in recent models by Neves ''et al.'' (2011): Jagged 1 functions through lateral induction to activate Notch signalling. Notch signalling then functions through lateral inhibition and regulates Sox2 expression. Sox2 specifies sensory fate within the prosensory domains. "This confines sensory competence to the prosensory patches, ensuring the development of sensory organs of the correct size and location." <ref name="PMID21266409"/>

'''Establishing polarity and formation of inner ear structures'''
[[File:z3333865.gene expression.jpeg|thumb|300px|Representative expression patterns of genes controlling cochlear and vestibular specification.]]

The different axis of the inner ear are fixed at different points in time. This means different signals are involved to establish the polarity and allow for development.<ref><pubmed>9389659</pubmed></ref>
The dorsal-ventral polarity is very significant in the development of inner ear structures. The ventral inner ear consists of the cochlea and saccule, and the dorsal inner ear is made up of semicircular canals, endolymphatic duct, cristae and utricle.

The neural tube plays a role in patterning of the placode and it has been shown similar signals from the neural tube are also needed to establish the dorso-ventricular axis of the inner ear.<ref><pubmed>16325169 </pubmed></ref>

* ''Shh signalling''
The notochord produces Shh, which helps in patterning the dorso-ventricular axis of the neural tube. <ref><pubmed>18621990</pubmed></ref> This signal diffuses further and also affects the developing otocyst, where a gradient of Shh receptors is located from the dorsal to ventral aspect. <ref><pubmed>12231626</pubmed></ref>
Dorso-ventricular patterning and development of inner ear structures – in particular ventral structures – is achieved by the graded response to Shh.

As reviewed by Grooves and Fekete (2012) “data suggests that Shh acts on the ventral otocyst directly to regulate cochlear development, and that dorsal development can be regulated by signals from tissues adjacent to the otocyst that require Shh signaling for their normal development.”<ref name="PMID22186725"><pubmed>22186725</pubmed></ref>

* ''Wnt signalling''
Shh signalling for the ventral aspect is complemented by signals for the dorsal aspect of the inner ear. Wnt signalling takes places in the otic placode, as described above. This is initially as a gradient from medial to lateral <ref><pubmed>20171206 </pubmed></ref>, which later in the otocyst will be a gradient from doral to ventral <ref><pubmed>16452098</pubmed></ref>

As further suggested in the review by Grooves and Fekete (2012) “Wnt and Shh signals regulate different inner ear genes in different ways, with opposing gradients of Shh and Wnt signaling regulating the spatial localization of transcription factors, ultimately leading to the differentiation of a correctly patterned inner ear.” <ref name="PMID22186725"/>

* ''Hedgehog signalling''
It is also crucial for normal development of inner ear structures that Hedgehog signalling is repressed. <ref><pubmed>20223756</pubmed></ref>

====Summary inner ear====

{| cellpadding=5 style="border:2px solid #00FF00"
|- bgcolor= #CCFF00
|'''SUMMARY OF THE INNER EAR'''
|- bgcolor=#E7FEFF
|
* Development of the inner ear: This starts out with the induction of the otic placode and consists of 3 major stages
'''1.''' Pre-placodal domain: After gastrulation, a pre-placodal domain is present adjacent to the anterior neural plate. The various placodes will arise from this domain.

'''2.''' Pre-otic field: Local signals establish the identity of each placode, including the otic placode. FGF signals from both rhombomeres and the cranial paraxial mesoderm are important otic inducers.

'''3.''' Otic placode/epidermis fate decision: signalling occurs to determine precisely which cells become the otic placode and which cells aquire the epidermal fate. FGF and Wnt signalling is necessary in this step, which could possibly be dependent or independent of each other.

* Neural component: During the early stages of embryonic development, a neural competent domain is established as part of the otic placode. FGF, Sox and Notch signalling play a role in creating and maintaining this domain. Once invagination occurs and an otocyst has formed, signalling pathways allow for patterning of the otocyst and formation of prosensory patches. Hair cells develop from the sensory patches and neurons develop from the remaining neural competent domain.

* Establishing polarity and formation of inner ear structures: The ventral inner ear consists of the cochlea and saccule, and the dorsal inner ear is made up of semicircular canals, endolymphatic duct, cristae and utricle. For this reason, it is important for normal development of the inner ear to establish polarity, such as the dorso-ventral axis. Various signals are involved, including Shh and Wnt signalling. Hedgehog signalling needs to be suppressed.
|}

==Abnormal Hearing==

===Genetic===

{| cellpadding=5 style="border:1px solid #fad67d"
|- bgcolor="#FFA500"
|'''Genetic abnormality'''||'''Description'''||'''Image'''
|- bgcolor="#FFEFD5"
|''Mutation of GJB2 gene'' ||
* Approximately 60% of congenital deafness in developed nations is caused by genetic factors.
* More than 50 loci have been found to be responsible for the genetic causes of non syndromic deafness (isolated hearing loss with no affects to other parts of the body) called NSD and accounts for more than 80% of genetic related congenital deafness. GJB2 gene which instructs the protein Connexin 26 to be formed, is the most common cause of NSD.
* Connexin 26 is found all over the body, with a great number on the skin and in the inner ear.
*Over 90 of the GJB2 gene mutations have been associated with NSD. <ref><pubmed> 10980526 </pubmed></ref>

||
[[File:Mutation_on_GJB2_gene.jpg|x250px]]

|- bgcolor="#FFCC99"
|''Autosomal dominant hearing loss'' ||
* Autosomal dominant hearing loss is transferred directly though the previous generations and can usually be detected when reviewing at a family tree.
* There is a 50% probability that the child will also have hearing loss, and subsequently increases if both parents have the dominant gene. Research has shown that the phenotype due to GJB2 varies due to the great range of the degree of deafness in the patients.
* This alludes to the fact that other environmental causes have also contributed to the patients hearing impairment <ref><pubmed> 10980526 </pubmed></ref>.
* M34T missense mutation has been found in families where there are both affected and non affected people thus indicating its contribution to autosomal deafness both dominant and recessive deafness.
* Similarly, studies have shown additional missense mutations R75W, D66H and G59A are also causes of DNFA however they have been connected to other clinical manifestations <ref><pubmed> 11216656 </pubmed></ref>.

||
[[File:Dominant_diagram.jpg|x250px]]

|- bgcolor="#FFEFD5"
|''Autosomal recessive hearing loss'' ||
* Autosomal recessive deafness is an inheritance of both the mother and father’s recessive genes of connexin 26 mutation.
* There is a 25% chance that the child will have hearing loss. However normally as both parents have normal hearing, it is difficult to foresee if the child will inherit hearing loss.
* The most prevalent connexin 26 gene mutation in the majority of ethnic groups for DNFB is the 35delG.
* Mutations in the connexin 26 genes equate to half of the DNFB cases <ref><pubmed> 14979964 </pubmed></ref>.

||
[[File:Autosomal_Recessive_Inheritance_Diagram.jpg|x250px]]

|- bgcolor="#FFCC99"
|''X linked hearing loss'' ||
* X linked hearing loss is carried by the mother and passed down to both the male and female children.
* Generally only the male children are affected if they receive the affected X chromosome while the daughters will be the carrier of the gene.
* The hearing loss can be a combination of both conductive (damage to the outer or middle ear) and sensorineural hearing loss (malfunction of the cochlea and or the hearing nerve) <ref><pubmed> 1163535 </pubmed></ref>.

||
[[File:X_Linked_Recessive_Diagram.jpg|x250px]]

|- bgcolor="#FFEFD5"
|''Mitochondrial hearing loss'' ||
* Mitochondrial hearing loss is passed down solely through the mother.
* It is caused by mutations in either MT-RNR1 or MT-TS1 leading to moderate to profound hearing loss.
* MT RNR1 is generally correlated to aminoglycoside ototoxicity and sensorineural hearing loss independent of aminoglycoside ototoxicity occurring usually in the 20’s.
*Aminoglycoside ototoxicity refers to the increased chance of hearing loss after consuming antibiotics and is irreversible.
* MT-TS1 is sensorineural hearing loss occurring during childhood and is generally considered nonsyndromic <ref><pubmed> 20301595 </pubmed></ref>.

|}

NOTE: DEFINITIONS OF SYNDROMIC AND NON SYNDROMIC HEARING LOSS

'''Genetic Syndromes'''

{| cellpadding=5 style="border:1px solid #fad67d"
|- bgcolor="#FFF000"
|'''Syndrome'''||'''Description'''||'''Image'''
|- bgcolor="#FFFDD0"
|''Usher Syndrome'' ||
* Most common cause of congenital deafness due to defects in the inner ear and also causes vision loss
* Separated into 3 subgroups: USH1, USH2 and USH3<ref><pubmed> 16434480 </pubmed></ref>.

## USH1 - profound deafness at birth
## USH2 - Moderate level of deafness at birth
## USH3 - Hearing normal at birth but will gradually worsen as the child ages
* Various genes are thought to cause the disorder most recent is WHRN gene <ref><pubmed> 16452831 </pubmed></ref>.

||
[[File:Basal_Cochlear_Outer_Hair_Cells.jpg|x250px]]
|- bgcolor="#FBEC5D"
|''Pendred Syndrome'' ||
* Autosomal recessive disorder which causes progressive sensorineural hearing loss, and can also affect the thyroid gland, accounting for more than 10% of severe hearing impairment.
* Patients usually have structural malformations of the inner ear, in some cases a missing cochlear.
* The syndrome is caused by a variety of gene mutations, SLC26A4 gene causing more than half of all of the Pendred Syndrome cases.
* There is no current treatment option, and is most important that it is screened for in childhood hearing loss in order to teach differing ways of communication <ref><pubmed> 18285825 </pubmed></ref>.

'''All of these defects are suggestive of a developmental arrest at 7 weeks of human embryonic development. In addition, it has been noted that patients with Mondini malformations usually have reduced numbers of hair cells and spiral ganglion cells (11); these latter microscopic defects are thought to lead to the deafness. '''

||
[[File:Pendred_Syndrome_Showing_Mondini_Defects.jpg|x450px]]
|- bgcolor="#FFFDD0"
|''Goldenhar Syndrome'' ||
* There are a varying amount of malformations usually regarding the ears, mouth and jaw such as microtia and preauricular appendages.
* There is limited knowledge as to how this syndrome occurs, and there are currently no treatments for the subsequent hearing loss. <ref><pubmed>10829494 </pubmed></ref>
* It is thought that environment could play a role with an increased level of children developing this syndrome during the Golf War <ref><pubmed> 9408975 </pubmed></ref>.

||
[[File:MRI_of_Goldenhar_Syndrome.jpg]]

|}

===Environmental===

'''Infections'''

{| cellpadding=5 style="border:1px solid #74C365"
|- bgcolor="#009F6B"
|'''Organism'''||'''Description'''||'''
|- bgcolor="#F0FFF0"
|''Toxoplasmosis'' ||
* Toxoplasma gondii is an intracellular protozoan and can infect humans through undercooked meat containing bradyzoites or by legumes infected by oocysts (greatly infectious).
* A study published in 1988 collected data from 23,000 pregnancies which found mothers with an IgG antibody to toxoplasmosis during pregnancy doubled the incidence of deafness for the child. This was identified along with other symptoms such as microcephaly and low IQ scoring. It was also identified that 15 of the 23,000 pregnancies vertical transmission of the child contracting congenital toxoplasmosis.
* Congenital toxoplasmosis also results in mental retardation and deafness along with blindness and usually multiple organs affected such as Chorioretinitis. Notably, the infection risk differs during the gestation time: “1% at less than 6 weeks, 4–6% at 6–16 weeks, 20–40% at 16–25 weeks and 60–80% at 36 weeks of gestation” (http://www.marmaramedicaljournal.org/pdf/pdf_MMJ_446.pdf)
* Detection of toxoplasmosis is achived through amniocentesis and subsequently using PCR to determine a positive result from DNA amplification <ref><pubmed> 3041362 </pubmed></ref>.
* Although presently there are no known vaccines to prevent congenital toxoplasmosis, the treatment of pyrimethamine-sulfadiazine or spiramycin had been recommended to reduce the chance of the presumed infected mother passing on the disease to the child <ref><pubmed> 10356003 </pubmed></ref>.
*There have been inconclusive and inconsistent treatment investigations suggested to be caused by limited randomised controlled trials <ref><pubmed> 9988811 </pubmed></ref>. Although presently there are no known vaccines to prevent congenital toxoplasmosis, the treatment of pyrimethamine-sulfadiazine or spiramycin had been recommended to reduce the chance of the presumed infected mother passing on the disease to the child <ref><pubmed> 11561963 </pubmed></ref>.
* Notably, although this was an uncontrolled trial, this prenatal treatment was proven to be of some benefit <ref><pubmed> 10356003 </pubmed></ref> <ref><pubmed> 12618153 </pubmed></ref> <ref><pubmed> 1929726 </pubmed></ref> <ref><pubmed> 11821335 </pubmed></ref>.

|- bgcolor="#AAF0D1"
|''Rubella'' ||
* In 1979 an article was published in the Lancet providing clear evidence of the direct link between rubella and sensorineural deafness finding 24% of the hearing impaired children tested had the rubella antibody.
* Studies have subsequently shown that the fetal infection risk will differ throughout the duration of the pregnancy. During week 1 to 10, there is a 100% fetal transmission rate, leading to an 81% rate during the first trimester, due to the immaturity of the fetal defense mechanisms and solely relying on maternal immunoglobulin G. This decreases throughout the second and third trimester, however the infection rate goes back to 100% in the last month of pregnancy. The sudden decrease is thought to be due by the maternal antibodies along with fetal cell mediated immune responses along with the humoral responses.
*Rubella infects the placenta via maternal viraemia which leads to necrotic areas in the chorionic villae epithelium. (G Tondury, DW Smith Fetal rubella pathology). As the cells appear desquamated within the vessel lumens, it is thought that the rubella virus is passed through the fetal circulation via endothelial cell emboli, which in turn leads to an increase in infection and damage to the developing fetal organs.
* Fetal organ development may be compromised by the virus prompting apoptosis. Studies indicate that the caspid protein dependent mechanism of the Rubella virus leads to apoptosis. (Rubella Virus Capsid Protein Induces Apoptosis in Transfected RK13 Cells, Robert Duncan). Rubella infected cells which do not undergo apoptosis result in a reduced growth rate and a shorten life span due to a decreased mitotic activity.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation.
* As Rubella has long been a known congential disease, through the Rubella vaccine, this has almost completely eliminated the disease in western countries. Thus as this is an entirely preventable disease, future programs should of Rubella prevention should lead to Rubella being a disease of the past.

(Rubella, the lancet, DWG Brown AND KV Pugachev, TK Frey Rubella virus induces apoptosis in culture cells)

(Onset and severity of hearing loss due to congenital rubella infection)

|- bgcolor="#F0FFF0"
|''Cytomegalovirus'' ||
* Cytomegalovirus (CMV) is an enveloped herpes virus which is passed to the fetus via vertical transmission.
* As 95% of pregnant women are asymptomatic, it is incredibly hard to diagnose.
* The virus can be classified into acute and non acute infections. Acute maternal infection can be verified by low IgG avidity levels.
* There are 2 methods to determine if the fetus has contracted CMV. A cordocentesis can be conducted to obtain fetal blood for sampling however issues have been raised regarding its safety and notably accessibility. (Weiner C.P.: Cordocentesis. Obstet Gynecol Clin North Am 15. 283-301.1988).
* Amniocentesis can also diagnose the CMV via PCR and is considered the better diagnostic tool due to the quick and reliable results it gives. High DNA copy numbers for the CMV infection relates to a greater severity of the disease and hence could indicate the hearing impairment outcome.
* A recent study has noted the role of CMV causing sensorineural hearing loss and subsequently being a high risk factor for hearing impairment. The results showed that more than half of the children participating had CMV IgG antibodies, with 20% being found as CMV DNA positive which indicates that the child has an active infection. (Congenital cytomegalovirus infection – a common cause of hearing loss of unknown aetiology, Eva Karltorp).
* There is no current treatment protocol for CMV, however a non random sampling trial has suggested the treatment of hyperimmune globulin giving promising results in the study. (Nigro G., Adler S.P., La Torre R., et al: Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med 353. 1350-1362.2005; ).
* Another study showed that treatment of the symptomatic cases of CMV infection with intravenous ganciclovir (or Valganciclovir orally) for 6 weeks has indicated improvement in the child’s hearing. (Oliver SE, Cloud GA, Sanchez PJ, Demmler GJ, Dankner W, Shelton M, et al. Neurodevelopmental outcomes following ganciclovir therapy in symptomatic congenital cytomegalovirus infections involving the central nervous system. J Clin Virol 2009;46S:S22-S6.)

|}

'''Drugs'''

{| cellpadding=5 style="border:1px solid #FF0090"
|- bgcolor="#FF55A3"
|'''Drug'''||'''Description'''||'''
|- bgcolor="#FFA6C9"
|''Alcohol consumption during pregnancy'' ||
* Fetal Alcohol syndrome is a variety of conditions which occur in the fetus if the mother consumes alcohol during pregnancy. There is no safe level of alcohol consummation during pregnancy.
*Fetal Alcochol Syndrome is associated to 4 hearing impairment disorders:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss
(Hearing, speech, language, and vestibular disorders in the fetal alcohol syndrome: a literature review. Church MW, Kaltenbach JA Alcohol Clin Exp Res 1997 May;21(3):495-512.)
*It is also associated with a variety of other malformations (skeletal and visceral), growth retardation and nervous system defects. The developmental delay of the auditory system is thought to be due to decreased growth of neurons and myelin and subsequently the synapses.
* Sensorineural hearing loss is thought to be caused by a greater amount of apoptosis during the inner ear development and thus leading to decreased levels of auditory nerve fibres and sensory receptor cells. Intermittent conductive hearing loss is thought to be due to poorly formed eustachian tube.
* Finally, the central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing.

|- bgcolor="#FFF0F5"
|''Isotretinoin'' ||
*

|}

===Structural malformations of the ear===

{| cellpadding=5 style="border:1px solid #880085"
|- bgcolor="#9457EB"
|'''Structural malformation'''||'''Description'''||'''Image'''
|- bgcolor="#FAF5FF"
|''Stenosis'' ||
* Internal auditory canal stenosis is classified as someone who has an internal auditory canal 2mm or less.
* It is considered a rare disease with only 2.5% of patients with congenital hearing loss being affected by stenosis .
* It is thought to be as secondary to vestibulocochlear nerve hypoplasia <ref><pubmed> 9892864 </pubmed></ref>.

||
[[File:Bilateral_Stenosis_of_Internal_Auditory_canal.jpg|x230px]]
|- bgcolor="#E0CEF2"
|''Enlarged vestibular aqueduct'' ||
* Approximately 7% of all sensorineural hearing loss patients had an enlarged vestibular aqueduct.
* The most recognised cause of an enlarged vestibular aqueduct is due to a mutation on chromosome 7 on the SLC26A4 gene <ref><pubmed> 16570074 </pubmed></ref>.
* There is no current treatment and thus is important to identify it when the patient is a child so that alternative communicative methods can be taught.

(Sensorineural hearing loss in Patients with large vestibular aqueduct, Okumura)

||
[[File:Enlarged_Vestibular_aqueduct.jpg|x250px]]
|- bgcolor="#FAF5FF"
|''Microtia''||
* Deformation of the outer ear which can be with or without the external ear canal.
*There are 4-5 grades of microtia which range from a small ear to deformed outer ear to no ear present at all.
* Treatment involves the complete reconstruction of the outer ear and occasionally the middle ear depending on the level of hearing loss associated with it <ref><pubmed> 10890145 </pubmed></ref>.

||
[[File:Microtia_boy_surgery.jpg|x320px]]

|}

---------

==Technologies to detect==

The importance of having a neonatal screening test for hearing within the early days of life are important for the rest of that individual’s life. Screening is used to identify the children most at risk of having a congenital hearing problem. The importance of having an early diagnosis and having a method of intervention is crucial for the development of speech and language and learning of the child later in life, as reviewed by Oudesluys-Murphy ‘’et al’’. 1996. <ref name="PMID8789756"><pubmed>8789756</pubmed></ref>
Screening tests allow for the detection of hearing loss within the few days of life. This could be due to a dysfuctional cochlea or various other problems as discussed in our abnormal hearing section. Within Australia there are a few simple test that allow newborns to be tested fast, accurately and reliable <ref name="PMID8789756"/>.

===Oto-acoustic testing===
[[File: infant hearing test.jpg|thumb|300px| Testing the hearing of an infant]]

The oto-acoustic test measures the integrity of the inner ear. This involves the cochlea and its physiological effects - the production of an otoacoustic emission in response to sound <ref name="PMID8220282"><pubmed>8220282</pubmed></ref>. It involves inserting a probe into the ear canal, which then produces clicks or tones that are normally picked up by the cochlea. The function and healthiness of the cochlea can be measured, as the different parts of the cochlea respond to different forms of stimuli in terms on pitch and frequency <ref name="PMID8220282"/>.

For this test, there are two methods used for screening the hearing in newborns.

• The production of a single click or tone called the Transient Evoked Otoacoustic Emission test (TEOAE) <ref name="PMID8220282"/>

• The production of two simultaneous tones named the Distortion Product Otoacoustic Emissions Test (DPOAE) <ref name="PMID8220282"/>

===Auditory Brainstem Response===

The Auditory Brainstem Response tests the neurological function of the auditory brainstem. It is more so used as a referral test, rather than a screening test, as generally hearing loss is already suspected <ref name="PMID11667937"><pubmed>11667937</pubmed></ref>. This test uses a click or a tone, which causes the production of impulses by the neurons from the auditory nerve, travelling along the auditory pathway. This is then measured and detected by external electrodes that are on the scalp and the earlobe of the newborn. <ref name="PMID11667937"/>

===Automated Brainstem Response===

This cheaper and quicker method uses an ear cup that is fitted over the infant’s ear <ref name="PMID11343042"><pubmed>11343042</pubmed></ref>. This then sends out a stimulus and a response is measured through a series of electrodes that are connected to the earlobes, scalp, shoulders and neck<ref name="PMID11343042"/>. The automated brainstem response uses a computer to visualise and calculate the results, and produce a result of either ‘pass/refer’. Data of the patient are cross-referenced with a collection of results regarded as normal responses<ref name="PMID11343042"/>.

===OtoSCOPE===

A new genetic testing method called OtoSCOPE discovered in 2010 has greatly increased the efficiency for testing nonsyndromic hearing loss and Usher syndrome. It provides a great diagnostic tool, as all the genes related to hearing loss can be sequenced simultaneously thereby decreasing cost and time. The patients can be informed relatively early for any genetic abnormalities therefore providing early prognosis and genetic counselling. <ref><pubmed>21078986</pubmed></ref>

==Technologies to overcome the problems==
Depending on the hearing loss, there are different types of technologies to overcome this. Types of hearing lost are conductive and sensori-neutral . One type is the conductive, caused by the damage or blockage of the outer or middle ear, the other is sensori-neutral, where the damage is to the auditory pathway or nerve. In some cases there is a combination of the two. And there are two current technologies that overcome this problem and they are the the hearing aid and the cochlea ear implant.

===Hearing aid===
[http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx Hearing Aids] are a major advance in helping people hearing, they work by amplifying the sounds so they can be detected even by the damaged inner ear. This method of hearing relies on the healthiness or still relative functioning cochlea. The damage of the sensori-neural pathway is overcome by the amplication of sounds to compensate the loss of hearing cells or hair cells in the cochlea. This is proportionate to the amount of hair cells still functioning. This amplication of the sounds, helps the patient hear and listen and communicate with others. This however also amplifies background noise. They consists of the microphone, amplifier and a speaker. From the sound being received by the microphone, this converted by the microphone into electrical impulses and replays it to the amplifer. The amplifier sends the impulses though the speaker into the ear as an increased sound.
<ref name="NIH">{{citation
|title= Hearing Aid Basics
|url=http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx
|publisher = National Institute of Health
|accessdate =September 19, 2012}}</ref>

===Cochlea Ear Implant===
[http://www.nidcd.nih.gov/health/hearing/pages/coch.aspx Cochlea ear] implants help the hearing impaired to listen. This is through having a device to provide a sense of sound. The cochlea implants consists of a few major components in helping the patient hear. It consists of a microphone, which detects the environmental sounds, a small electronic processor that selects the sound produced from the microphone. There is also a transmitter and the stimulator. This converts the signal that comes off the electronic processor into electrical impulses, which leads up the final component which is the electrode array. This picks up the electrical impulses and delivers them to the correct region of the auditory nerve. These methods of hearing or sensing sound are used only in severer or profoundly hearing impaired who have a dysfunctioning cochlea. <ref><pubmed>PMID:6028666</pubmed></ref>

<ref name='cochlea_NPR'>{{cite=book| first=Hendrinkus| last=Dulfhuis|coauthors=| title=''Cochlea Mechanics: Introduction to a time Domain Analysis of Cochlea''| date=10-2-2012| publisher Springer Science+ Business Media|url=http://books.google.com.au/books?id=1UpECoc_q3UC&pg=PA5&lpg=PA5&dq=Gabriele+Falloppio+ear&source=bl&ots=mc9sb_0UR1&sig=WqdWXmDrJWV-2rqlWF3ihzMnWLE&hl=en&sa=X&ei=ozFoUPL8BoiQiQf_qoDYDw&ved=0CEEQ6AEwAw#v=onepage&q=Gabriele%20Falloppio%20ear&f=false| work=cochlea implant| pages = | accessdate = 20012-10-01 | language = }}</ref>

==Current Research==

* ''' ''Hair cell differentiation'' '''

A recently published paper by Pan ''et al.'' (2012) investigated the various levels and durations of expression of a particular transcription factor, which is necessary for hair cell differentiation. The ''Atoh1'' transcription factor was tested for by using conditional knock-out mice - ''Atoh1-cre'' <ref name="PMID22279587"><pubmed>22279587</pubmed></ref>. They determined that reduced levels of ''Atoh1'' resulted in the progressive loss of hair cells from the organ of Corti shortly after birth <ref name="PMID22279587"/>. Similar data was obtained when the deletion of the ''Atoh1'' transcription factor was delayed. Slight differences were noted between inner and outer hair cells: the loss of inner hair cells was more significant than the loss of outer hair cells. This indicates that ''Atoh1'' may play a role in the differential development of inner and outer hair cells.
[[File: Atoh1 model.png|left|thumb|225px|Atoh1-cre is expressed in hair cells and causes transient limited expression of Atoh1 in CKO ears.]]
[[File: Atoh1 hair cell loss.png|none|thumb|200px|Conditional deletion of Atoh1 results in death of organ of Corti cells and patchy Myo7a-positive presumptive hair cells which are innervated by many nerve fibers.]]

* ''' ''Stem cell therapy'' '''

The discovery of stem cells has led to an entirely new era in research, and the potential to prevent and treat conditions such as hearing loss.
It has been discovered that stem cells are present in the inner ear. In non-mammalian vertebrates, these stem cells allow the inner ear sensory epithelium to recover and function again after being damaged. This is not the case when it comes to mammals. Cells capable of regeneration are found in the vestibular sensory epithelium and in the neonatal cochlea. <ref><pubmed>8456285</pubmed></ref> However, only very limited regeneration may take place after damage has been done to the inner ear. Research is ongoing in various laboratories worldwide, such as at the University of Sheffield, as to how stem cells can be used to regain the sense of hearing. Early September 2012 there was an incredible breakthrough, as scientists from the university used [http://www.actiononhearingloss.org.uk/news-and-events/all-regions/press-releases/human-stem-cells-restore-hearing.aspx human embryonic stem cells to restore hearing in a common form of deafness.] This proves human stem cells could be used to repair the damaged ear and will hopefully lead to various other stem-cell based therapies.

[[File: aquaporins.png|thumb|200px|Aquaporins]]

* ''' ''Middle ear homeostasis'' '''

A recent article by Morris ''et al.'' (2012) investigated the mechanisms responsible for the ion homeostasis in the middle ear and how this relates to disease. They used BALB/c mice for immunohistochemistry of particular ion homeostasis factors of the middle and inner ear <ref name="PMID22720014"><pubmed>22720014</pubmed></ref>. This was then used to compare transport and barrier mechanisms and identify what is present in the tympanic cavity. Next, the middle ears received transtympanic injections with heat-killed Haemophilus influenza to determine if these channels are impacted by inflammation <ref name="PMID22720014"/>. Data shows that cellular hypertrophy occurred and localization of ion channels, such as aquaporins, was preserved within the inflamed middle ear epithelium<ref name="PMID22720014"/>. Morris ''et al.'' suggested that these channels could be used as a therapeutic target.

* ''' ''Molecular mechanisms - ongoing project'' '''

The HEARing Cooperative Research Centre ([http://www.hearingcrc.org/ CRC]) is involved in many ongoing research projects. Professor Doug Hilton supervises one of the projects: Genomic & molecular therapeutic approaches to environmental and age-related hearing loss.

A major public health issue is presbycusis - age-related hearing loss. It is known that apoptosis of cells within the cochlea plays a role; however, the many other factors involved and their molecular mechanisms are not yet fully understood. This research project is looking at the genes, proteins and regulatory pathways involved in both hearing and hearing-loss. The aim is to use this knowledge to identify molecules that can be targeted to [http://www.hearingcrc.org/research/projects/r122 prevent and/or treat hearing loss.]

==Glossary==

*'''Cristae''': the sensory organ of rotation located in the semicircular canal of the inner ear

*'''Ectoderm''': the outermost layer of the three primary germ cell layers in the very early embryo

*'''Epidermis''': surface epithelium of the skin, superficial to the dermis

*'''Gastrulation''': The inward migration of cells

*'''Hindbrain''': The lower part of the brainstem, comprising the cerebellum, pons, and medulla oblongata

*'''Lateral inhibition''': process whereby one cell takes on a state and the adjacent cells takes on the opposite state

*'''Mesoderm''': the middle layer of the three primary germ cell layers in the very early embryo

*'''Neural plate''': a thickened plate of ectoderm along the dorsal midline of the early vertebrate embryo that gives rise to the neural tube and crests

*'''Neural tube''': A hollow structure formed after gastrulation, from which the brain and spinal cord form

*'''Open neural plate stage''': stage of the neural plate before closure into the neural tube

*'''Otic placode''': a thickening of the ectoderm on the outer surface of a developing embryo from which the ear develops

*'''Otocyst – otic vesicle''': The structure formed by invagination of the embryonic ectodermal tissue that develops into the inner ear

*'''Pre-placodal domain''': An ectodermal domain with multipotential progenitors that contribute to sense organs and cranial sensory ganglia

*'''Proneural region – neural competent domain''': a region of the otic placode involved in neurogenesis

*'''Prosensory region''': region containing a population of cells that can develop into hair cells or or supporting cells

*'''Rhombomere''': a segment of the developing rhombencephalon (hindbrain segment)

*'''Saccule''': one of two otolith organs. The smaller of the two fluid-filled cavities forming part of the labyrinth of the inner ear

*'''Somite''': A segmental mass of mesoderm in the vertebrate embryo, occurring in pairs along the notochord

*'''Utricle''': one of two otolith organs. The larger of the two fluid-filled cavities forming part of the labyrinth of the inner ear

*'''Vestibular region''': the region of the inner ear close to the cochlea. Here the semicircular canals converge

*'''Vestibulo-acoustic ganglion''': The cranial ganglion of cranial nerve 8

==External Links==

[http://news.yale.edu/2012/02/16/yale-study-how-mitochondrial-dna-defects-cause-inherited-deafness|Yale study: how mitochondrial DNA defects cause inherited deafness]

== References ==
<references/>

==External Links==
{{External Links}}

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 6

2012-10-02T05:43:41Z

Z3333794: /* Adult Ear: Overview of Anatomy and Physiology */

[[File: z3333865.Ruby.jpeg | 450px| right]]
= Hearing Development=

==Introduction==

CAN YOU HEAR ME! – Hearing is one of the most important sense and an inherent part of human life. It widens our scope of life and allows us to work, relax, communicate, learn and form memories. The sense of hearing has evolved through the years in vertebrates is inherent for both hunting and surviving. The sound energy produced has be converted into an electrical signal for us to make sense of it. For successful transmission the correct development of the ear is of utmost important. Not only formation of the structures but also their correct assembly is imperative to normal ear functioning. In this project we will discuss the development of human ear from implantation to birth by shining light on the differentiation of cells and signalling mechanisms that lead to normal development. We will also talk about some abnormal processes and mutations which lead to various structural and functional diseases.

==History==

{| cellpadding=5 style="border:2px solid #08E8DE"
|- bgcolor= #00BFFF
|'''Date''' || '''Description'''
|- bgcolor=#87CEEB
|'''1536''' || The first clear distinction is made between the middle and inner ear. How to observe the middle ear ossicles is also explained. <ref><pubmed>4598483</pubmed></ref> <ref name="PMID6341584"><pubmed>6341584</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1438986/?page=6 Nicola Massa.]
|- bgcolor=#ADD8E6
| '''1543''' || ''De fabrica'' by Andreas Vesalius was published which identified and named the incus and the malleus. Also identified the tensor tympani and the anatomical position of the oval window to the round window <ref><pubmed>22581496</pubmed></ref>. [http://www.ncbi.nlm.nih.gov/pubmed/22581496 Andreas Vesalius]
|- bgcolor=#87CEEB
|''' 1561''' || ''Observationes anatomicae'' is published and describes the tympanic membrane. The stapes ossicle is also discovered and named. <ref><pubmed>22965774</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pubmed/22965774 Gabriele Falloppio]
|- bgcolor=#ADD8E6
| '''1563''' || In the book ''De Auditus Organis'', it was proposed that the tympanic membrane is connected to the nasopharynx. This tube was named after the writer of the book. He also completed the diescritpion of the tensor tymapani: <ref><pubmed>7029021</pubmed></ref>[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142106 Bartolomeo Eustachi]
|- bgcolor=#87CEEB
|'''17th Century'''|| The Metal ear was one of the first hearing aids created. It was placed over the ear to channel sound into the ear.
|- bgcolor=#ADD8E6
| '''1648''' ||Athanasius Kircher describes the ear trumpet: [http://www.ncbi.nlm.nih.gov/pubmed/10986798 Athanasius Kircher]
|- bgcolor=#87CEEB
|'''1683''' || The bony labyrinth is described in more detail. It is determined the spiral lamina has a bony and membranous part, and it divides the spiral duct into an upper and lower compartment. <ref name="PMID6341584"/>[http://www.sciencedirect.com/science/article/pii/S1286011510000172 Duverney.]
|- bgcolor=#ADD8E6
|'''1704'''|| The book ''De aure humana tractatus'' with information regarding the anatomy, physiology and pathology of the ear is published.<ref name="PMC1142106"><pubmed>PMC1142106</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142106/ Valsalva.]
|- bgcolor= #87CEEB
|'''1707'''|| It is proposed that the labyrinth contains fluid instead of air. <ref name="PMC1142106"/> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142106/ Valsalva.]
|- bgcolor=#ADD8E6
| '''1772'''|| Antonio Scarpa discovers the ear labyrinth <ref><pubmed>11314703</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pubmed/11314703 Scarpa.]
|- bgcolor= #87CEEB
|'''1789'''|| The membranous labyrinth is shown to consist of semicircular canals and the vestibular sacs. These form one system and are different to the periosteum. <ref><pubmed>11314703</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pubmed/11314703 Scarpa.]
|- bgcolor=#ADD8E6
| '''1831''' || It was discovered that the membranous labyrinth develops from a pit in the skin.It was also discovered that the spiral lamina is hollow. <ref><pubmed>1910378</pubmed></ref> [http://www.encyclopedia.com/doc/1G2-2830902099.html Huschke.]
|- bgcolor=#87CEEB
| '''1851''' || The cochlea is discovered in the inner ear, and parts of it, including the sensory epithelium, the spiral ganglion, the tectorial membrane, and the stria vascularis are described. [http://www.ncbi.nlm.nih.gov/pubmed/3517746 Alfonso Corti.]
|- bgcolor=#ADD8E6
|'''1898'''|| The first electric hearing aid, the Akouphone, was developed. A carbon transmitter allowed the hearing aid to be portable. [http://www.earhelp.co.uk/who-was-miller-reese-hutchinson.html Miller Reese Hutchison.]
|- bgcolor=#87CEEB
|'''1961'''|| Georg Von Békésy was awarded the Nobel Prize in Physiology or Medicine. He was awarded on this research on the sound waves at different frequencies on the nerve fibres. the research showed that the hair cells were activated along the cochlea correlated to the position of the cochlea. [http://www.ncbi.nlm.nih.gov/pubmed/14584991 Georg Von Békésy.]
|- bgcolor=#ADD8E6
|'''1978'''|| For the first time, a cochlear implant allowed a person to hear again. [http://www.abc.net.au/gnt/profiles/Transcripts/s1117832.htm Professor Graeme Clark.]
|- bgcolor=#87CEEB
| '''2012'''|| For the first time, human embryonic stem cells were used and proven to be effective in restoring hearing. See Current Research below and the [http://www.actiononhearingloss.org.uk/news-and-events/all-regions/press-releases/human-stem-cells-restore-hearing.aspx news article.]
|}

==Adult Ear: Overview of Anatomy and Physiology==

[[File:Anatomy_of_the_Ear.JPG|thumb|left|350px|Anatomy of the ear]]

In order for mammals to hear, sound energy in the air has to move the hair cells located inside the inner ears of mammals. The ear provides us with the suitable apparatus to convert the longitudinal sound waves into mechanical ones in order to move the hair cells located in the inner ear. The Pinna or the auricle is designed such that the sound waves coming in get directed into the external auditory meatus. The waves travel through the EAM hit the tympanic membrane or eardrum, which causes it to vibrate. The malleus, which is in contact with the tympanic membrane, moves which in turn moves the other ossicles. The ossicles namely malleus, incus and stapes provide solid medium for the waves to travel through and act as a lever increasing the amplitude of the sound wave 20 times.

[[File:Histology_of_Inner_Ear.png|thumb|right|300px|Histology of Inner Ear]]

The oval window marks the boundary between the middle and the inner ear, which constitutes of an outer bony labyrinth and an inner membranous labyrinth. The cochlea which is a coil resembling a snail’s shell houses the organ of Corti, the peripheral receptor for hearing. Histologically the cochlea is divided into 3 parts scala vestibule, scala media and the scala tympani divided by the vestibular and basilar membrane respectively.

The sound waves are transmitted from the stapes into the oval window. The vibrations cause movement of the perilymph fluid in the scala vestibuli into the scala media causing movement of basilar membrane and bending of the hair cells. The bending of the cells causes them to activate which sends signals down the vestibulocochlear nerve. The nerve impulses travel from this neve through the brainstem to the thalamus to the primary auditory cortex, which is located on the transverse temporal gyrus.

The basilar membrane has a tonotopic organisation and human ears can hear sounds ranging from 20-20000 Hz. Near the apex of the cochlea the basilar membrane is wide and loose whereas near the base is narrow and tight hence enabling us to hear different frequencies.

==Development==

The development of outer ear is attributed to the first pharyngeal arch. All the germ layer namely endoderm, mesoderm and ectoderm contribute to its formation. <ref><pubmed>8287791</pubmed></ref>

The pharyngeal arches arise as a series of bulges arising laterally from the embryo head around 3-4 weeks of human development. The arches have a consistent organisation of the endoderm, ectoderm and mesoderm. The ectoderm forms the outer surface of the arch with the core made up of mesoderm. Next to the mesoderm core on the opposite the ectoderm is the endoderm. All three layers contribute to the formation of outer, middle and inner ear structures hence contributing to hearing. In between the arches the ectoderm and endoderm come in contact with each other forming a continuous sheath on either side of the mesoderm, forming groves externally and arches internally. Inside the mesoderm core of each arch lies a specific cell population that goes onto develop into a nerve, cartilage and artery.

===Outer Ear===

'''Pinna'''

[[File:Devt_of_external_ear.JPG|thumb|400px|The image depicts the development of the pinna through the fetal development stages]]

Post development the anatomy of the external ear simply consists of the pinna or the auricle and external acoustic/auditory meatus. The auricle develops around the first and second pharyngeal arches as a series of auricular enlargements or hillocks around the 5th week of development. Gradually by the 6th week the hillocks grow in size and increase to six in number, three on the first arch and 3 on the second arch, the first of which starts at the bottom anterior side going in a clockwise direction. In the 7th week the hillocks enlarge further and each of the arches contributes to a specific part of the pinna. The first arch gives rise to the tragus, helix and cymba concha whereas arch 2 gives rise to concha, antihelix and antitragus. The differentiation starts around the neck region but as the mandible develops the pinna structures move more cranially. It is not until the 12th week that the fusion of these various parts occur and is completed by week 20th.

Various genetic markers and coordinated signalling mechanisms are required for normal development of the pinna. One of which is the EYA1 gene, which is imperative for formation of the pinna. Mice with a homologous Eya1 null gene either has malformed or absent ears and since Eya1 gene plays a role in the formation of cartilage, its absence doesn’t allow the ear mesenchyme to convert into ear cartilage. Another gene important for pinna cartilage formation is the Bmp5 gene that is expressed later in development, mutation in which causes malformation of the perichondrium and thus cartilage formation. Another gene important for early patterning of the pinna is the Hox2 gene, mutations in which leads to formation of a shapeless protuberance rather than a normal shaped pinna. Hox2 gene is expressed in the second pharyngeal arch and the malformations in the ear are contributed to the parts derived from the second pharyngeal arch like the antitragus, antihelix and concha.
<ref><pubmed>14674478</pubmed></ref> <ref><pubmed>17104502</pubmed></ref>

'''External Auditory Meatus'''

The External Auditory Meatus (EAM) is derived from ectoderm that forms the first pharyngeal groove situated between the 1st and the 2nd pharyngeal arches. At 8 weeks of gestation a c-shaped skeletal structure develops from ectoderm of the first pharyngeal cleft migrating and meeting the mesoderm of the first grove called the tympanic ring that controls and coordinates the invagination of the ectoderm. The tympanic ring is a transient embryological structure, which eventually gets integrated into the temporal bone and provides anchorage to the eardrum. Medial to the ring lays the endoderm of the first pharyngeal arch that contributes to the formation of the tympanic or middle ear cavity. At 12 weeks of gestation the tympanic ring begins to ossify in a sequential fashion via endomembranous ossification forming the bony part of the EAM. The ring starts to condense at the proximal end of the 1st pharyngeal arch, goes around the circumference of the cleft and invades the 2nd arch. Starting at the tip of the 1st pharyngeal cleft the ectodermal cells begin to proliferate filling the lumen of the meatus forming a meatal plug which medially extends in a disc like fashion during week 10. The proliferation follows the path of the tympanic ring with the mesoderm tissue between the ring and the meatus forming a fibrous layer. In week 13 of development the innermost part of the meatal plug makes a contact with malleus. This innermost part of the disc in week 15 splits leaving a thin endoderm layer behind which contributes to formation of the tympanic membrane. By the middle of 16th week the meatus although full in length is still narrow and curved and it is not until week 18 that it gets fully expanded and complete.

Since the correct development of EAM is heavily dependent on the tympanic ring, hence any mutation in the tympanic ring causes an abnormal growth of the EAM. Many genes are required to coordinate and control tympanic ring formation most prominent being the Gsc and Prx1 genes. Chimeric studies have revealed that tympanic ring in Gsc null mice fails to ossify whereas the ring whereas mice with null Prx1 gene have an over ossified tympanic ring. In both cases the meatus fails to form indicating a delicate balance between the expressions of both genes is required for proper ring development hence correct formation of EAM. Likewise for pinna formation Hox2 gene is also essential for differentiation of pharyngeal arch into the tympanic ring and the formation of EAM. <ref><pubmed>10976045</pubmed></ref> <ref><pubmed>14674478</pubmed></ref> <ref><pubmed>1441991</pubmed></ref>

===Middle Ear===

'''Tympanic Membrane'''

Tympanic membrane or the eardrum forms the boundary between the outer and middle ear and responsible for transmitting the soundwaves coming in from the EAM to the mechanical waves going into the ossicles. During 8th week of gestation the development of tympanic membrane begins when the first funnel shaped ectodermal cleft meets the endodermal pouch with the mesenchyme growing in-between. This mesenchyme eventually becomes thinner and forms the eardrum during week 12. The diameter of the membrane grows three fold between week 11 and 16 and the membrane fuses with the tympanic ring.

The 1st pharyngeal cleft (ectoderm) gives rise to the EAM and the tympanic membrane comes from the mesoderm from the 1s pharyngeal arch. The 1st pharyngeal pouch (endodermal in origin) proliferates to giving rise to the tubotympanic recess at 3rd gestational week. During week 7 the 2nd pharyngeal arch constricts the tympanic recess dividing it into a medial portion that form the Eustachian tube and a lateral portion that forms the tympanic cavity. <ref><pubmed> 17346562</pubmed></ref> <ref><pubmed> 10976045</pubmed></ref> <ref><pubmed> 2921547</pubmed></ref>

'''The Ossicles'''

The middle ear constitutes of the skeletal structures called ossicles, which amplify and transmit sound to the inner ear.

The middle ear consists of the middle ear cavity and it are housed the 3 ossicles – the malleus, incus and stapes from lateral to medial. The mesenchymal tissue or the neural crest cells from 1st and 2nd pharyngeal arch contributes to the formation of the ossicular chain.

Two main theories underlie the formation of the ossicles. First is the classical theory according to which the malleus and incus develops from the first pharyngeal arch whereas stapes develops from the 2nd pharyngeal arch. Another theory proposes that malleal head and body of incus comes from the first pharyngeal arch while the second arch gives rise to stapes, handle of malleus and long process of incus. <ref><pubmed>18803631</pubmed></ref>.

[[File:normal cochlea.png |thumb|150px|Wild-type inner ear showing normal morphology]]

===Inner Ear===

The entire inner ear, as well as the neurons which innervate the sensory organ, are derived from the otic placode.
The otic placode is a thickened portion of ectoderm located on the each side of the developing head of the embryo, next to the hindbrain. It is generally visible after gastrulation, once the first 5 to 10 pairs of somites have formed. Invagination occurs next, which creates the otocyst - a vesicle which will develop into the different components of the inner ear: the cochlea, the semicircular canals with cristae, the utricle, the saccule and the vestibulo-acoustic ganglion. <ref name="PMID17891709"><pubmed>17891709</pubmed></ref>[[File:z3333865.stages development inner ear.jpg|thumb|300px|Developmental milestones in mouse inner ear formation]]

====The Otic Placode====

'''Induction of the otic placode'''

Experiments with molecular markers have revealed that several steps are needed for induction of the otic placode.

We will briefly consider the three major steps:

'''1''' ''Pre-placodal domain''

The pre-placodal domain is a narrow strip of the ectoderm adjacent to the anterior neural plate after gastrulation. Different placodes arise from the pre-placodal domain. All the craniofacial sensory organs, including the ear, develop from these different placodes located at the periphery of the neural plate.

Various evidence indicates the existence of this pre-placodal region:

* Morphology indicates a thickened band of ectoderm around the anterior neural plate in some species, including mice and humans. As time progresses, this thickening will only be present at the locations where the different craniofacial placodes differentiate - including the otic placode.<ref><pubmed>15531360</pubmed></ref>

* Experiments have also shown that the placodes will only develop in the correct location, if rotation of the ectoderm along the anteroposterior axis takes place at the open neural plate stage. If rotation takes place at a later time, the placodes will form at incorrect places.<ref><pubmed>14100031</pubmed></ref>

* Gene expression has also indicated that particular genes are present in the pre-placodal domain. These genes belong to the Dlx, Six, Eya, Iro, BMP, Foxi and Msx families. Glavic et al. (2004) has shown that 'loss and gain of function of some of these genes resulted in the widening or reduction of the pre-placodal field'. Linked to this was also the domain of expression of some placode-specific genes; which either enlarged or diminished.<ref><pubmed>15242793</pubmed></ref>

'''2''' ''Pre-otic field''
[[File:z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared]]

Once the general placodal state has been established, the identity of each placode is induced by local signals. The optic placode is induced by various signals, including Pax8, Pax2, Fibroblast Growth Factors (FGFs), and many transciption factors.

In particular the FGFs are significant otic inducers. Signalling occurs from various rhombomeres from the hindbrain and the cranial paraxial mesoderm located beneath the area of the otic placode. For example, in mice FGF3 is expressed in rhombomeres
5 and 6, whereas FGF10 is expressed in the underlying mesoderm.<ref><pubmed>7789270</pubmed></ref> <ref name="PMID12810586"><pubmed>12810586</pubmed></ref> Mutations of FGF3 and FGF10 have been investigated. Results showed that mice with a mutation of either FGF3 or FGF10 developed an abnormal otic vesicle, and a combination of the two mutants resulted in failure to form an otic vesicle.<ref name="PMID12810586"/>

''--> picture''

'''3''' ''Otic placode/epidermis fate decision''

In the presence of FGF signalling, Wnt signalling can significantly influence the next step, which is the otic placode/epidermis fate decision. According to the review article by Ohyama ''et al''. (2007) ‘Cells receiving high levels of Wnt signalling differentiate as otic placode, while cells receiving little or no Wnt signalling differentiate as epidermis.’<ref name="PMID17891709"/>

The first evidence regarding the contribution of Wnt signalling came from experiments with the otic ectoderm of chicks.
* Data showed that specific marker genes, such as Pax2, were induced to a greater extend with FGF19 and Wnt8c present as compared to FGF19 alone <ref><pubmed>11110663</pubmed></ref>. Ladher ''et al''.(2000) hypothesised that FGF19 induced Wnt8c, and together they induced the otic gene markers.

Another possibility is the independent action of FGFs and Wnt signalling.
* Studies have shown that Wnt signalling onto Pax2+ cells results in differentiation of those cells into otic placode tissue. Pax2+ cells that were not exposed to Wnt signalling differentiate as epidermis <ref name="PMID16452098"><pubmed>16452098</pubmed></ref>.
* Wnt signalling also suppresses Foxi2, resulting in a Foxi2-negative area of particular size, which then allows for FGFs to induce otic genes <ref name="PMID16452098"/>. In this case, Wnt signalling determined the size of the otic placode, yet acted independently from FGF signalling.
* Phillips et al. (2004) studied the role of FGF and Wnt signalling; specifically looking at FGF3, FGF8 and Wnt8. Their data showed that Wnt8 is not absolutely necessary for otic induction, however it is required for timely initiation of the otic field. <ref><pubmed>14757644</pubmed></ref>

'''The neural domain'''
[[File:neural domain.jpg|thumb|200px|The expression of Sox2 and Sox3 during development of the ear]]
During the early stages of embryonic development, a neural competent domain is established. This domain will eventually give rise to neurons and hair cells. Various signalling pathways are required to initially create this domain and to maintain it later on. <ref name="PMID19247974"><pubmed>19247974</pubmed></ref>

* ''FGF and Sox''
FGF signalling and the Sox genes are essential for the establishment of the neural competent domain. An important aspect of Sox genes is that they have a state of self-renewal, as well as a state of neural commitment. <ref><pubmed>15863505</pubmed></ref>
As investigated by Rex et al. (1997) and Pevny and Placzek (2005), "SoxB1 genes (Sox1, Sox2, Sox3) have been linked directly to ectodermal cells that are competent to acquire neural fate, and the commitment of cells to a neural fate".<ref><pubmed>9215646</pubmed></ref> <ref><pubmed>15721738</pubmed></ref>

Before the otic placode becomes distinct, Sox3 is already expressed in a broad area around the location of the future otic placode. Later in it will only be found in the proneural region of the otic placode. Based on this, the review by Alsina et al. (2009) suggests that a neural fate acquisition occurs prior to otic placode formation.<ref name="PMID19247974"/> During the early stages of development of the otocyst, Sox2 and Sox3 are found in proliferating cells within the proneural region. Both are expressed when neurons are generated, however, Sox3 switches off and only Sox2 remains during further development of the ear. This suggests that the ongoing expression of Sox2 plays a role in sensory cell development, as explained in the review by Alsina et al (2009).<ref name="PMID19247974"/>

-We will look into this in further detail when describing the development of the elementary sensory unit of the ear-

* ''Notch signalling''
Notch signalling is required for several developmental processes, including the maintenance of the neural competent domain.

In the notch signalling pathway, notch is the receptor, with most of its ligands being transmembrane proteins. Signalling is therefore restricted to neighbouring cells. Research by Daudet and Lewis (2005) reveiled how notch signalling plays a role in inner ear development, including:

- Notch signalling mediates lateral inhibition and thereby controls the differentiation of hair cells and supporting cells - in particular in the vestibular regions <ref name="PMID15634704"><pubmed>15634704</pubmed></ref>

- An early phase of Notch activity promotes formation of prosensory patches <ref name="PMID15634704"/>

- Other signalling pathways are likely to cooperate with Notch to specify prosensory regions of the otocyst <ref name="PMID15634704"/>

====The Otocyst====
[[File:neural fate.jpg|thumb|200px|Recent model related to sensory fate.]]

'''Patterning of the otocyst'''

The otocyst, also known as the otic vesicle, is present once invagination of the otic placode has occurred. Regionalisation of the otocyst results in the topological organisation of the ear. The neural tube affects the patterning of the otocyst, and FGF, Wnt and Hh signalling pathways are also known to play a role.
FGF and Wnt rely on signals from the hindbrain. <ref><pubmed>17891710</pubmed></ref>

Prosensory patches emerge within the otocyst. These develop as a differentiate from the neural competent domain.<ref name="PMID21266409"><pubmed>21266409</pubmed></ref>

- haircells (sensory patch)

- neurons (neural competent domain)

As proposed in recent models by Neves ''et al.'' (2011): Jagged 1 functions through lateral induction to activate Notch signalling. Notch signalling then functions through lateral inhibition and regulates Sox2 expression. Sox2 specifies sensory fate within the prosensory domains. "This confines sensory competence to the prosensory patches, ensuring the development of sensory organs of the correct size and location." <ref name="PMID21266409"/>

'''Establishing polarity and formation of inner ear structures'''
[[File:z3333865.gene expression.jpeg|thumb|300px|Representative expression patterns of genes controlling cochlear and vestibular specification.]]

The different axis of the inner ear are fixed at different points in time. This means different signals are involved to establish the polarity and allow for development.<ref><pubmed>9389659</pubmed></ref>
The dorsal-ventral polarity is very significant in the development of inner ear structures. The ventral inner ear consists of the cochlea and saccule, and the dorsal inner ear is made up of semicircular canals, endolymphatic duct, cristae and utricle.

The neural tube plays a role in patterning of the placode and it has been shown similar signals from the neural tube are also needed to establish the dorso-ventricular axis of the inner ear.<ref><pubmed>16325169 </pubmed></ref>

* ''Shh signalling''
The notochord produces Shh, which helps in patterning the dorso-ventricular axis of the neural tube. <ref><pubmed>18621990</pubmed></ref> This signal diffuses further and also affects the developing otocyst, where a gradient of Shh receptors is located from the dorsal to ventral aspect. <ref><pubmed>12231626</pubmed></ref>
Dorso-ventricular patterning and development of inner ear structures – in particular ventral structures – is achieved by the graded response to Shh.

As reviewed by Grooves and Fekete (2012) “data suggests that Shh acts on the ventral otocyst directly to regulate cochlear development, and that dorsal development can be regulated by signals from tissues adjacent to the otocyst that require Shh signaling for their normal development.”<ref name="PMID22186725"><pubmed>22186725</pubmed></ref>

* ''Wnt signalling''
Shh signalling for the ventral aspect is complemented by signals for the dorsal aspect of the inner ear. Wnt signalling takes places in the otic placode, as described above. This is initially as a gradient from medial to lateral <ref><pubmed>20171206 </pubmed></ref>, which later in the otocyst will be a gradient from doral to ventral <ref><pubmed>16452098</pubmed></ref>

As further suggested in the review by Grooves and Fekete (2012) “Wnt and Shh signals regulate different inner ear genes in different ways, with opposing gradients of Shh and Wnt signaling regulating the spatial localization of transcription factors, ultimately leading to the differentiation of a correctly patterned inner ear.” <ref name="PMID22186725"/>

* ''Hedgehog signalling''
It is also crucial for normal development of inner ear structures that Hedgehog signalling is repressed. <ref><pubmed>20223756</pubmed></ref>

====Summary inner ear====

{| cellpadding=5 style="border:2px solid #00FF00"
|- bgcolor= #CCFF00
|'''SUMMARY OF THE INNER EAR'''
|- bgcolor=#E7FEFF
|
* Development of the inner ear: This starts out with the induction of the otic placode and consists of 3 major stages
'''1.''' Pre-placodal domain: After gastrulation, a pre-placodal domain is present adjacent to the anterior neural plate. The various placodes will arise from this domain.

'''2.''' Pre-otic field: Local signals establish the identity of each placode, including the otic placode. FGF signals from both rhombomeres and the cranial paraxial mesoderm are important otic inducers.

'''3.''' Otic placode/epidermis fate decision: signalling occurs to determine precisely which cells become the otic placode and which cells aquire the epidermal fate. FGF and Wnt signalling is necessary in this step, which could possibly be dependent or independent of each other.

* Neural component: During the early stages of embryonic development, a neural competent domain is established as part of the otic placode. FGF, Sox and Notch signalling play a role in creating and maintaining this domain. Once invagination occurs and an otocyst has formed, signalling pathways allow for patterning of the otocyst and formation of prosensory patches. Hair cells develop from the sensory patches and neurons develop from the remaining neural competent domain.

* Establishing polarity and formation of inner ear structures: The ventral inner ear consists of the cochlea and saccule, and the dorsal inner ear is made up of semicircular canals, endolymphatic duct, cristae and utricle. For this reason, it is important for normal development of the inner ear to establish polarity, such as the dorso-ventral axis. Various signals are involved, including Shh and Wnt signalling. Hedgehog signalling needs to be suppressed.
|}

==Abnormal Hearing==

===Genetic===

{| cellpadding=5 style="border:1px solid #fad67d"
|- bgcolor="#FFA500"
|'''Genetic abnormality'''||'''Description'''||'''Image'''
|- bgcolor="#FFEFD5"
|''Mutation of GJB2 gene'' ||
* Approximately 60% of congenital deafness in developed nations is caused by genetic factors.
* More than 50 loci have been found to be responsible for the genetic causes of non syndromic deafness (isolated hearing loss with no affects to other parts of the body) called NSD and accounts for more than 80% of genetic related congenital deafness. GJB2 gene which instructs the protein Connexin 26 to be formed, is the most common cause of NSD.
* Connexin 26 is found all over the body, with a great number on the skin and in the inner ear.
*Over 90 of the GJB2 gene mutations have been associated with NSD. <ref><pubmed> 10980526 </pubmed></ref>

||
[[File:Mutation_on_GJB2_gene.jpg|x250px]]

|- bgcolor="#FFCC99"
|''Autosomal dominant hearing loss'' ||
* Autosomal dominant hearing loss is transferred directly though the previous generations and can usually be detected when reviewing at a family tree.
* There is a 50% probability that the child will also have hearing loss, and subsequently increases if both parents have the dominant gene. Research has shown that the phenotype due to GJB2 varies due to the great range of the degree of deafness in the patients.
* This alludes to the fact that other environmental causes have also contributed to the patients hearing impairment <ref><pubmed> 10980526 </pubmed></ref>.
* M34T missense mutation has been found in families where there are both affected and non affected people thus indicating its contribution to autosomal deafness both dominant and recessive deafness.
* Similarly, studies have shown additional missense mutations R75W, D66H and G59A are also causes of DNFA however they have been connected to other clinical manifestations <ref><pubmed> 11216656 </pubmed></ref>.

||
[[File:Dominant_diagram.jpg|x250px]]

|- bgcolor="#FFEFD5"
|''Autosomal recessive hearing loss'' ||
* Autosomal recessive deafness is an inheritance of both the mother and father’s recessive genes of connexin 26 mutation.
* There is a 25% chance that the child will have hearing loss. However normally as both parents have normal hearing, it is difficult to foresee if the child will inherit hearing loss.
* The most prevalent connexin 26 gene mutation in the majority of ethnic groups for DNFB is the 35delG.
* Mutations in the connexin 26 genes equate to half of the DNFB cases <ref><pubmed> 14979964 </pubmed></ref>.

||
[[File:Autosomal_Recessive_Inheritance_Diagram.jpg|x250px]]

|- bgcolor="#FFCC99"
|''X linked hearing loss'' ||
* X linked hearing loss is carried by the mother and passed down to both the male and female children.
* Generally only the male children are affected if they receive the affected X chromosome while the daughters will be the carrier of the gene.
* The hearing loss can be a combination of both conductive (damage to the outer or middle ear) and sensorineural hearing loss (malfunction of the cochlea and or the hearing nerve) <ref><pubmed> 1163535 </pubmed></ref>.

||
[[File:X_Linked_Recessive_Diagram.jpg|x250px]]

|- bgcolor="#FFEFD5"
|''Mitochondrial hearing loss'' ||
* Mitochondrial hearing loss is passed down solely through the mother.
* It is caused by mutations in either MT-RNR1 or MT-TS1 leading to moderate to profound hearing loss.
* MT RNR1 is generally correlated to aminoglycoside ototoxicity and sensorineural hearing loss independent of aminoglycoside ototoxicity occurring usually in the 20’s.
*Aminoglycoside ototoxicity refers to the increased chance of hearing loss after consuming antibiotics and is irreversible.
* MT-TS1 is sensorineural hearing loss occurring during childhood and is generally considered nonsyndromic <ref><pubmed> 20301595 </pubmed></ref>.

|}

NOTE: DEFINITIONS OF SYNDROMIC AND NON SYNDROMIC HEARING LOSS

'''Genetic Syndromes'''

{| cellpadding=5 style="border:1px solid #fad67d"
|- bgcolor="#FFF000"
|'''Syndrome'''||'''Description'''||'''Image'''
|- bgcolor="#FFFDD0"
|''Usher Syndrome'' ||
* Most common cause of congenital deafness due to defects in the inner ear and also causes vision loss
* Separated into 3 subgroups: USH1, USH2 and USH3<ref><pubmed> 16434480 </pubmed></ref>.

## USH1 - profound deafness at birth
## USH2 - Moderate level of deafness at birth
## USH3 - Hearing normal at birth but will gradually worsen as the child ages
* Various genes are thought to cause the disorder most recent is WHRN gene <ref><pubmed> 16452831 </pubmed></ref>.

||
[[File:Basal_Cochlear_Outer_Hair_Cells.jpg|x250px]]
|- bgcolor="#FBEC5D"
|''Pendred Syndrome'' ||
* Autosomal recessive disorder which causes progressive sensorineural hearing loss, and can also affect the thyroid gland, accounting for more than 10% of severe hearing impairment.
* Patients usually have structural malformations of the inner ear, in some cases a missing cochlear.
* The syndrome is caused by a variety of gene mutations, SLC26A4 gene causing more than half of all of the Pendred Syndrome cases.
* There is no current treatment option, and is most important that it is screened for in childhood hearing loss in order to teach differing ways of communication <ref><pubmed> 18285825 </pubmed></ref>.

'''All of these defects are suggestive of a developmental arrest at 7 weeks of human embryonic development. In addition, it has been noted that patients with Mondini malformations usually have reduced numbers of hair cells and spiral ganglion cells (11); these latter microscopic defects are thought to lead to the deafness. '''

||
[[File:Pendred_Syndrome_Showing_Mondini_Defects.jpg|x450px]]
|- bgcolor="#FFFDD0"
|''Goldenhar Syndrome'' ||
* There are a varying amount of malformations usually regarding the ears, mouth and jaw such as microtia and preauricular appendages.
* There is limited knowledge as to how this syndrome occurs, and there are currently no treatments for the subsequent hearing loss. <ref><pubmed>10829494 </pubmed></ref>
* It is thought that environment could play a role with an increased level of children developing this syndrome during the Golf War <ref><pubmed> 9408975 </pubmed></ref>.

||
[[File:MRI_of_Goldenhar_Syndrome.jpg]]

|}

===Environmental===

'''Infections'''

{| cellpadding=5 style="border:1px solid #74C365"
|- bgcolor="#009F6B"
|'''Organism'''||'''Description'''||'''
|- bgcolor="#F0FFF0"
|''Toxoplasmosis'' ||
* Toxoplasma gondii is an intracellular protozoan and can infect humans through undercooked meat containing bradyzoites or by legumes infected by oocysts (greatly infectious).
* A study published in 1988 collected data from 23,000 pregnancies which found mothers with an IgG antibody to toxoplasmosis during pregnancy doubled the incidence of deafness for the child. This was identified along with other symptoms such as microcephaly and low IQ scoring. It was also identified that 15 of the 23,000 pregnancies vertical transmission of the child contracting congenital toxoplasmosis.
* Congenital toxoplasmosis also results in mental retardation and deafness along with blindness and usually multiple organs affected such as Chorioretinitis. Notably, the infection risk differs during the gestation time: “1% at less than 6 weeks, 4–6% at 6–16 weeks, 20–40% at 16–25 weeks and 60–80% at 36 weeks of gestation” (http://www.marmaramedicaljournal.org/pdf/pdf_MMJ_446.pdf)
* Detection of toxoplasmosis is achived through amniocentesis and subsequently using PCR to determine a positive result from DNA amplification <ref><pubmed> 3041362 </pubmed></ref>.
* Although presently there are no known vaccines to prevent congenital toxoplasmosis, the treatment of pyrimethamine-sulfadiazine or spiramycin had been recommended to reduce the chance of the presumed infected mother passing on the disease to the child <ref><pubmed> 10356003 </pubmed></ref>.
*There have been inconclusive and inconsistent treatment investigations suggested to be caused by limited randomised controlled trials <ref><pubmed> 9988811 </pubmed></ref>. Although presently there are no known vaccines to prevent congenital toxoplasmosis, the treatment of pyrimethamine-sulfadiazine or spiramycin had been recommended to reduce the chance of the presumed infected mother passing on the disease to the child <ref><pubmed> 11561963 </pubmed></ref>.
* Notably, although this was an uncontrolled trial, this prenatal treatment was proven to be of some benefit <ref><pubmed> 10356003 </pubmed></ref> <ref><pubmed> 12618153 </pubmed></ref> <ref><pubmed> 1929726 </pubmed></ref> <ref><pubmed> 11821335 </pubmed></ref>.

|- bgcolor="#AAF0D1"
|''Rubella'' ||
* In 1979 an article was published in the Lancet providing clear evidence of the direct link between rubella and sensorineural deafness finding 24% of the hearing impaired children tested had the rubella antibody.
* Studies have subsequently shown that the fetal infection risk will differ throughout the duration of the pregnancy. During week 1 to 10, there is a 100% fetal transmission rate, leading to an 81% rate during the first trimester, due to the immaturity of the fetal defense mechanisms and solely relying on maternal immunoglobulin G. This decreases throughout the second and third trimester, however the infection rate goes back to 100% in the last month of pregnancy. The sudden decrease is thought to be due by the maternal antibodies along with fetal cell mediated immune responses along with the humoral responses.
*Rubella infects the placenta via maternal viraemia which leads to necrotic areas in the chorionic villae epithelium. (G Tondury, DW Smith Fetal rubella pathology). As the cells appear desquamated within the vessel lumens, it is thought that the rubella virus is passed through the fetal circulation via endothelial cell emboli, which in turn leads to an increase in infection and damage to the developing fetal organs.
* Fetal organ development may be compromised by the virus prompting apoptosis. Studies indicate that the caspid protein dependent mechanism of the Rubella virus leads to apoptosis. (Rubella Virus Capsid Protein Induces Apoptosis in Transfected RK13 Cells, Robert Duncan). Rubella infected cells which do not undergo apoptosis result in a reduced growth rate and a shorten life span due to a decreased mitotic activity.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation.
* As Rubella has long been a known congential disease, through the Rubella vaccine, this has almost completely eliminated the disease in western countries. Thus as this is an entirely preventable disease, future programs should of Rubella prevention should lead to Rubella being a disease of the past.

(Rubella, the lancet, DWG Brown AND KV Pugachev, TK Frey Rubella virus induces apoptosis in culture cells)

(Onset and severity of hearing loss due to congenital rubella infection)

|- bgcolor="#F0FFF0"
|''Cytomegalovirus'' ||
* Cytomegalovirus (CMV) is an enveloped herpes virus which is passed to the fetus via vertical transmission.
* As 95% of pregnant women are asymptomatic, it is incredibly hard to diagnose.
* The virus can be classified into acute and non acute infections. Acute maternal infection can be verified by low IgG avidity levels.
* There are 2 methods to determine if the fetus has contracted CMV. A cordocentesis can be conducted to obtain fetal blood for sampling however issues have been raised regarding its safety and notably accessibility. (Weiner C.P.: Cordocentesis. Obstet Gynecol Clin North Am 15. 283-301.1988).
* Amniocentesis can also diagnose the CMV via PCR and is considered the better diagnostic tool due to the quick and reliable results it gives. High DNA copy numbers for the CMV infection relates to a greater severity of the disease and hence could indicate the hearing impairment outcome.
* A recent study has noted the role of CMV causing sensorineural hearing loss and subsequently being a high risk factor for hearing impairment. The results showed that more than half of the children participating had CMV IgG antibodies, with 20% being found as CMV DNA positive which indicates that the child has an active infection. (Congenital cytomegalovirus infection – a common cause of hearing loss of unknown aetiology, Eva Karltorp).
* There is no current treatment protocol for CMV, however a non random sampling trial has suggested the treatment of hyperimmune globulin giving promising results in the study. (Nigro G., Adler S.P., La Torre R., et al: Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med 353. 1350-1362.2005; ).
* Another study showed that treatment of the symptomatic cases of CMV infection with intravenous ganciclovir (or Valganciclovir orally) for 6 weeks has indicated improvement in the child’s hearing. (Oliver SE, Cloud GA, Sanchez PJ, Demmler GJ, Dankner W, Shelton M, et al. Neurodevelopmental outcomes following ganciclovir therapy in symptomatic congenital cytomegalovirus infections involving the central nervous system. J Clin Virol 2009;46S:S22-S6.)

|}

'''Drugs'''

{| cellpadding=5 style="border:1px solid #FF0090"
|- bgcolor="#FF55A3"
|'''Drug'''||'''Description'''||'''
|- bgcolor="#FFA6C9"
|''Alcohol consumption during pregnancy'' ||
* Fetal Alcohol syndrome is a variety of conditions which occur in the fetus if the mother consumes alcohol during pregnancy. There is no safe level of alcohol consummation during pregnancy.
*Fetal Alcochol Syndrome is associated to 4 hearing impairment disorders:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss
(Hearing, speech, language, and vestibular disorders in the fetal alcohol syndrome: a literature review. Church MW, Kaltenbach JA Alcohol Clin Exp Res 1997 May;21(3):495-512.)
*It is also associated with a variety of other malformations (skeletal and visceral), growth retardation and nervous system defects. The developmental delay of the auditory system is thought to be due to decreased growth of neurons and myelin and subsequently the synapses.
* Sensorineural hearing loss is thought to be caused by a greater amount of apoptosis during the inner ear development and thus leading to decreased levels of auditory nerve fibres and sensory receptor cells. Intermittent conductive hearing loss is thought to be due to poorly formed eustachian tube.
* Finally, the central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing.

|- bgcolor="#FFF0F5"
|''Isotretinoin'' ||
*

|}

===Structural malformations of the ear===

{| cellpadding=5 style="border:1px solid #880085"
|- bgcolor="#9457EB"
|'''Structural malformation'''||'''Description'''||'''Image'''
|- bgcolor="#FAF5FF"
|''Stenosis'' ||
* Internal auditory canal stenosis is classified as someone who has an internal auditory canal 2mm or less.
* It is considered a rare disease with only 2.5% of patients with congenital hearing loss being affected by stenosis .
* It is thought to be as secondary to vestibulocochlear nerve hypoplasia <ref><pubmed> 9892864 </pubmed></ref>.

||
[[File:Bilateral_Stenosis_of_Internal_Auditory_canal.jpg|x230px]]
|- bgcolor="#E0CEF2"
|''Enlarged vestibular aqueduct'' ||
* Approximately 7% of all sensorineural hearing loss patients had an enlarged vestibular aqueduct.
* The most recognised cause of an enlarged vestibular aqueduct is due to a mutation on chromosome 7 on the SLC26A4 gene <ref><pubmed> 16570074 </pubmed></ref>.
* There is no current treatment and thus is important to identify it when the patient is a child so that alternative communicative methods can be taught.

(Sensorineural hearing loss in Patients with large vestibular aqueduct, Okumura)

||
[[File:Enlarged_Vestibular_aqueduct.jpg|x250px]]
|- bgcolor="#FAF5FF"
|''Microtia''||
* Deformation of the outer ear which can be with or without the external ear canal.
*There are 4-5 grades of microtia which range from a small ear to deformed outer ear to no ear present at all.
* Treatment involves the complete reconstruction of the outer ear and occasionally the middle ear depending on the level of hearing loss associated with it <ref><pubmed> 10890145 </pubmed></ref>.

||
[[File:Microtia_boy_surgery.jpg|x320px]]

|}

---------

==Technologies to detect==

The importance of having a neonatal screening test for hearing within the early days of life are important for the rest of that individual’s life. Screening is used to identify the children most at risk of having a congenital hearing problem. The importance of having an early diagnosis and having a method of intervention is crucial for the development of speech and language and learning of the child later in life, as reviewed by Oudesluys-Murphy ‘’et al’’. 1996. <ref name="PMID8789756"><pubmed>8789756</pubmed></ref>
Screening tests allow for the detection of hearing loss within the few days of life. This could be due to a dysfuctional cochlea or various other problems as discussed in our abnormal hearing section. Within Australia there are a few simple test that allow newborns to be tested fast, accurately and reliable <ref name="PMID8789756"/>.

===Oto-acoustic testing===
[[File: infant hearing test.jpg|thumb|300px| Testing the hearing of an infant]]

The oto-acoustic test measures the integrity of the inner ear. This involves the cochlea and its physiological effects - the production of an otoacoustic emission in response to sound <ref name="PMID8220282"><pubmed>8220282</pubmed></ref>. It involves inserting a probe into the ear canal, which then produces clicks or tones that are normally picked up by the cochlea. The function and healthiness of the cochlea can be measured, as the different parts of the cochlea respond to different forms of stimuli in terms on pitch and frequency <ref name="PMID8220282"/>.

For this test, there are two methods used for screening the hearing in newborns.

• The production of a single click or tone called the Transient Evoked Otoacoustic Emission test (TEOAE) <ref name="PMID8220282"/>

• The production of two simultaneous tones named the Distortion Product Otoacoustic Emissions Test (DPOAE) <ref name="PMID8220282"/>

===Auditory Brainstem Response===

The Auditory Brainstem Response tests the neurological function of the auditory brainstem. It is more so used as a referral test, rather than a screening test, as generally hearing loss is already suspected <ref name="PMID11667937"><pubmed>11667937</pubmed></ref>. This test uses a click or a tone, which causes the production of impulses by the neurons from the auditory nerve, travelling along the auditory pathway. This is then measured and detected by external electrodes that are on the scalp and the earlobe of the newborn. <ref name="PMID11667937"/>

===Automated Brainstem Response===

This cheaper and quicker method uses an ear cup that is fitted over the infant’s ear <ref name="PMID11343042"><pubmed>11343042</pubmed></ref>. This then sends out a stimulus and a response is measured through a series of electrodes that are connected to the earlobes, scalp, shoulders and neck<ref name="PMID11343042"/>. The automated brainstem response uses a computer to visualise and calculate the results, and produce a result of either ‘pass/refer’. Data of the patient are cross-referenced with a collection of results regarded as normal responses<ref name="PMID11343042"/>.

===OtoSCOPE===

A new genetic testing method called OtoSCOPE discovered in 2010 has greatly increased the efficiency for testing nonsyndromic hearing loss and Usher syndrome. It provides a great diagnostic tool, as all the genes related to hearing loss can be sequenced simultaneously thereby decreasing cost and time. The patients can be informed relatively early for any genetic abnormalities therefore providing early prognosis and genetic counselling. <ref><pubmed>21078986</pubmed></ref>

==Technologies to overcome the problems==
Depending on the hearing loss, there are different types of technologies to overcome this. Types of hearing lost are conductive and sensori-neutral . One type is the conductive, caused by the damage or blockage of the outer or middle ear, the other is sensori-neutral, where the damage is to the auditory pathway or nerve. In some cases there is a combination of the two. And there are two current technologies that overcome this problem and they are the the hearing aid and the cochlea ear implant.

===Hearing aid===
[http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx Hearing Aids] are a major advance in helping people hearing, they work by amplifying the sounds so they can be detected even by the damaged inner ear. This method of hearing relies on the healthiness or still relative functioning cochlea. The damage of the sensori-neural pathway is overcome by the amplication of sounds to compensate the loss of hearing cells or hair cells in the cochlea. This is proportionate to the amount of hair cells still functioning. This amplication of the sounds, helps the patient hear and listen and communicate with others. This however also amplifies background noise. They consists of the microphone, amplifier and a speaker. From the sound being received by the microphone, this converted by the microphone into electrical impulses and replays it to the amplifer. The amplifier sends the impulses though the speaker into the ear as an increased sound.
<ref name="NIH">{{citation
|title= Hearing Aid Basics
|url=http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx
|publisher = National Institute of Health
|accessdate =September 19, 2012}}</ref>

===Cochlea Ear Implant===
[http://www.nidcd.nih.gov/health/hearing/pages/coch.aspx Cochlea ear] implants help the hearing impaired to listen. This is through having a device to provide a sense of sound. The cochlea implants consists of a few major components in helping the patient hear. It consists of a microphone, which detects the environmental sounds, a small electronic processor that selects the sound produced from the microphone. There is also a transmitter and the stimulator. This converts the signal that comes off the electronic processor into electrical impulses, which leads up the final component which is the electrode array. This picks up the electrical impulses and delivers them to the correct region of the auditory nerve. These methods of hearing or sensing sound are used only in severer or profoundly hearing impaired who have a dysfunctioning cochlea. <ref><pubmed>PMID:6028666</pubmed></ref>

<ref name='cochlea_NPR'>{{cite=book| first=Hendrinkus| last=Dulfhuis|coauthors=| title=''Cochlea Mechanics: Introduction to a time Domain Analysis of Cochlea''| date=10-2-2012| publisher Springer Science+ Business Media|url=http://books.google.com.au/books?id=1UpECoc_q3UC&pg=PA5&lpg=PA5&dq=Gabriele+Falloppio+ear&source=bl&ots=mc9sb_0UR1&sig=WqdWXmDrJWV-2rqlWF3ihzMnWLE&hl=en&sa=X&ei=ozFoUPL8BoiQiQf_qoDYDw&ved=0CEEQ6AEwAw#v=onepage&q=Gabriele%20Falloppio%20ear&f=false| work=cochlea implant| pages = | accessdate = 20012-10-01 | language = }}</ref>

==Current Research==

* ''' ''Hair cell differentiation'' '''

A recently published paper by Pan ''et al.'' (2012) investigated the various levels and durations of expression of a particular transcription factor, which is necessary for hair cell differentiation. The ''Atoh1'' transcription factor was tested for by using conditional knock-out mice - ''Atoh1-cre'' <ref name="PMID22279587"><pubmed>22279587</pubmed></ref>. They determined that reduced levels of ''Atoh1'' resulted in the progressive loss of hair cells from the organ of Corti shortly after birth <ref name="PMID22279587"/>. Similar data was obtained when the deletion of the ''Atoh1'' transcription factor was delayed. Slight differences were noted between inner and outer hair cells: the loss of inner hair cells was more significant than the loss of outer hair cells. This indicates that ''Atoh1'' may play a role in the differential development of inner and outer hair cells.
[[File: Atoh1 model.png|left|thumb|225px|Atoh1-cre is expressed in hair cells and causes transient limited expression of Atoh1 in CKO ears.]]
[[File: Atoh1 hair cell loss.png|none|thumb|200px|Conditional deletion of Atoh1 results in death of organ of Corti cells and patchy Myo7a-positive presumptive hair cells which are innervated by many nerve fibers.]]

* ''' ''Stem cell therapy'' '''

The discovery of stem cells has led to an entirely new era in research, and the potential to prevent and treat conditions such as hearing loss.
It has been discovered that stem cells are present in the inner ear. In non-mammalian vertebrates, these stem cells allow the inner ear sensory epithelium to recover and function again after being damaged. This is not the case when it comes to mammals. Cells capable of regeneration are found in the vestibular sensory epithelium and in the neonatal cochlea. <ref><pubmed>8456285</pubmed></ref> However, only very limited regeneration may take place after damage has been done to the inner ear. Research is ongoing in various laboratories worldwide, such as at the University of Sheffield, as to how stem cells can be used to regain the sense of hearing. Early September 2012 there was an incredible breakthrough, as scientists from the university used [http://www.actiononhearingloss.org.uk/news-and-events/all-regions/press-releases/human-stem-cells-restore-hearing.aspx human embryonic stem cells to restore hearing in a common form of deafness.] This proves human stem cells could be used to repair the damaged ear and will hopefully lead to various other stem-cell based therapies.

[[File: aquaporins.png|thumb|200px|Aquaporins]]

* ''' ''Middle ear homeostasis'' '''

A recent article by Morris ''et al.'' (2012) investigated the mechanisms responsible for the ion homeostasis in the middle ear and how this relates to disease. They used BALB/c mice for immunohistochemistry of particular ion homeostasis factors of the middle and inner ear <ref name="PMID22720014"><pubmed>22720014</pubmed></ref>. This was then used to compare transport and barrier mechanisms and identify what is present in the tympanic cavity. Next, the middle ears received transtympanic injections with heat-killed Haemophilus influenza to determine if these channels are impacted by inflammation <ref name="PMID22720014"/>. Data shows that cellular hypertrophy occurred and localization of ion channels, such as aquaporins, was preserved within the inflamed middle ear epithelium<ref name="PMID22720014"/>. Morris ''et al.'' suggested that these channels could be used as a therapeutic target.

* ''' ''Molecular mechanisms - ongoing project'' '''

The HEARing Cooperative Research Centre ([http://www.hearingcrc.org/ CRC]) is involved in many ongoing research projects. Professor Doug Hilton supervises one of the projects: Genomic & molecular therapeutic approaches to environmental and age-related hearing loss.

A major public health issue is presbycusis - age-related hearing loss. It is known that apoptosis of cells within the cochlea plays a role; however, the many other factors involved and their molecular mechanisms are not yet fully understood. This research project is looking at the genes, proteins and regulatory pathways involved in both hearing and hearing-loss. The aim is to use this knowledge to identify molecules that can be targeted to [http://www.hearingcrc.org/research/projects/r122 prevent and/or treat hearing loss.]

==Glossary==

*'''Cristae''': the sensory organ of rotation located in the semicircular canal of the inner ear

*'''Ectoderm''': the outermost layer of the three primary germ cell layers in the very early embryo

*'''Epidermis''': surface epithelium of the skin, superficial to the dermis

*'''Gastrulation''': The inward migration of cells

*'''Hindbrain''': The lower part of the brainstem, comprising the cerebellum, pons, and medulla oblongata

*'''Lateral inhibition''': process whereby one cell takes on a state and the adjacent cells takes on the opposite state

*'''Mesoderm''': the middle layer of the three primary germ cell layers in the very early embryo

*'''Neural plate''': a thickened plate of ectoderm along the dorsal midline of the early vertebrate embryo that gives rise to the neural tube and crests

*'''Neural tube''': A hollow structure formed after gastrulation, from which the brain and spinal cord form

*'''Open neural plate stage''': stage of the neural plate before closure into the neural tube

*'''Otic placode''': a thickening of the ectoderm on the outer surface of a developing embryo from which the ear develops

*'''Otocyst – otic vesicle''': The structure formed by invagination of the embryonic ectodermal tissue that develops into the inner ear

*'''Pre-placodal domain''': An ectodermal domain with multipotential progenitors that contribute to sense organs and cranial sensory ganglia

*'''Proneural region – neural competent domain''': a region of the otic placode involved in neurogenesis

*'''Prosensory region''': region containing a population of cells that can develop into hair cells or or supporting cells

*'''Rhombomere''': a segment of the developing rhombencephalon (hindbrain segment)

*'''Saccule''': one of two otolith organs. The smaller of the two fluid-filled cavities forming part of the labyrinth of the inner ear

*'''Somite''': A segmental mass of mesoderm in the vertebrate embryo, occurring in pairs along the notochord

*'''Utricle''': one of two otolith organs. The larger of the two fluid-filled cavities forming part of the labyrinth of the inner ear

*'''Vestibular region''': the region of the inner ear close to the cochlea. Here the semicircular canals converge

*'''Vestibulo-acoustic ganglion''': The cranial ganglion of cranial nerve 8

==External Links==

[http://news.yale.edu/2012/02/16/yale-study-how-mitochondrial-dna-defects-cause-inherited-deafness|Yale study: how mitochondrial DNA defects cause inherited deafness]

== References ==
<references/>

==External Links==
{{External Links}}

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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