Embryology - User contributions [en-gb]

User:Z3292017

2012-10-16T23:37:36Z

Z3292017: /* Lab Attendance */

=='''Lab Attendance'''==

Lab 1 - [[User:Z3292017|Z3292017]] 10:15, 25 July 2012 (EST)

Lab 2 - [[User:Z3292017|Z3292017]] 10:17, 1 July 2012 (EST)

Lab 3 - [[User:Z3292017|Z3292017]] 10:13, 8 August 2012 (EST)

Lab 4 - [[User:Z3292017|Z3292017]] 11:23, 15 August 2012 (EST)

Lab 5 - [[User:Z3292017|Z3292017]] 10:34, 22 August 2012 (EST)

Lab 6 - [[User:Z3292017|Z3292017]] 11:31, 29 August 2012 (EST)

Lab 7 - [[User:Z3292017|Z3292017]] 10:14, 12 September 2012 (EST)

Lab 8 - [[User:Z3292017|Z3292017]] 10:13, 19 September 2012 (EST)

Lab 9 - [[User:Z3292017|Z3292017]] 11:11, 26 September 2012 (EST)

Lab 10 - [[User:Z3292017|Z3292017]] 11:06, 3 October 2012 (EST)

Lab 11 - [[User:Z3292017|Z3292017]] 10:05, 10 October 2012 (EST)

Lab 12 - [[User:Z3292017|Z3292017]] 10:37, 17 October 2012 (EST)

==Lab 1 - [[User:Z3292017|Z3292017]]==

'''Lab 1 Online Assessment'''

''Question 1: Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique:''

The origin of IVF can be dated from the late 19th Century where embryo transplantation in rabbits was discovered by Walter Heape. The development of IVF was due to a cascade of events during the 20th century. Pincus and Enzmann from Harvard University suggested the possibility that mammalian eggs are able to develop normally in vitro in 1934. In 1948 Menken and Rock exposed 138 oocytes to spermatozoa in vitro. In 1959, Change was able to provide evidence for IVF by fertilising rabbit eggs with capicated sperm and thus achieve birth. From 1965 Robert Edwards attempted to fertilise human oocytes in vitro. In 1968 Edwards successfully fertilised a human egg using a human culture media he developed. Finally after years of research and failed attempts, the first test tube baby was born in 1978.
Robert Edwards was awarded the Nobel Prize in Physiology and Medicine in 2010 due to his immense development and contribution of IVF.

'''References'''
<references/>
#http://www.ivf-worldwide.com/ivf-history.html
#http://en.wikipedia.org/wiki/In_vitro_fertilisation
#http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/

''Question 2: Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings:''

Cleavage speed and implantation potential of early cleavage embryos in IVF or ICSI cycles by Lee, Lin and Hwu (July, 2012) attempted to determine the correlation of early embryo cleavage, its speed and the potential implantation rates for IVF. Their definition of early cleavage was embryonic mitosis occurring 25-27 hours after insemination. The embryos’ (day 3) cleavage speed was assessed and rated into 3 groups: rapid (more than 9 cells), normal (7-8 cells) and slow (less than 7 cells) along with their morphological quality being either good or poor. Normal fertilisation was determined by the presence of 2 nuclei and 2 polar bodies. 25-27 hours after IVF an early cleavage examination took place to determine which embryos had already cleaved. They embryos were then examined for their quality from 66-68 hours after IVF.

Early cleavage emrbyos developed normally in comparison to non early cleavage embryos. Notably, the early cleavage embryos produced a greater amount of “good quality” embryos and subsequently the implantation rate was sufficiently greater with early cleavage embryos. This finding is of great importance as embryo morphology is the most important tool to select the best embryo to transfer andthus increase the rates of implantation, pregnancy and live birth.

'''References'''

Lee MJ, Lee RK, Lin MH, Hwu YM '''Cleavage speed and implantation potential of early-cleavage embryos in IVF or ICSI cycles.''' J Assist Reprod Genet. 2012 Jul 25 PMID: 22825967

==Lab 2 - [[User:Z3292017|Z3292017]]==

'''Lab 2 Online Assessment'''

''Question 1: Image from journal source''

[[File:zygote.jpg]]

Zygotes showing different distribution of NPB in the 2PN and different PB alignment <ref>Alessia Nicoli, Francesco Capodanno, Lucia Moscato, Ilaria Rondini, Maria T Villani, Antonella Tuzio, and Giovanni B La Sala (2010) '''Analysis of pronuclear zygote configurations in 459 clinical pregnancies obtained with assisted reproductive technique procedures''' Department of Obstetrics and Gynecology, Arcispedale Santa Maria Nuova, Reprod Biol Endocrinol. 2010; 8: 77. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902489/?tool=pubmed NCBI]</ref>

===Reference===

<references/>

''Question 2: Identify a protein associated with the implantation process, including a brief description of the protein's role''

Proprotein convertase 6 (PC6) is a necessary regulatory molecule for embryo implantation which generates bioactive proteins such as growth factors, peptide hormones and adhesion molecules. It is produced in the uterine stromal cells in particular at the embryo attachment site throughout early pregnancy in mice. In order for implantation to occur, the uterus ungergoes morphological and physiological changes, one being differentiation of endometrial stromal cells.

Studies have shown that PC6 mRNA is upregulated in particularly at the site of embryo attachment in the mouse uterus, being predominantly at the antimesometrial pole undergoing decidualisation. These results imply that PC6 is associated with decidualisation. From this study, the researchers were able to determine that endometrial PC6 is imperative for maternal stromal decidual response for an implanting embryo during the time of implantation. They discovered that endometrial PC6 is produced explicitly in decidual cells (the vascular and cellular changes in a uterus in preparation for pregnancy) and is not found in other cells as well as the embryo. Similarly, they noted that inhibition of the production of PC6 early on (around day 3.5) using anti-PC6 MO blocked the decidualisation and thus impeded implantation. Notably, PC6 is produced in the late secretory phase of the menstrual cycle in preparation for implantation.

===Reference===

Guiying Nie, Ying Li, Min Wang, Yi Xun Liu, Jock K. Findlay and Lois A. Salamonsen '''Inhibiting Uterine PC6 Blocks Embryo Implantation: An Obligatory Role for a Proprotein Convertase in Fertility''' Biology of Reproduction April 1, 2005 vol. 72 no. 4 1029-1036. [http://www.biolreprod.org/content/72/4/1029.long Biology of Reproduction]

==Lab 3 - [[User:Z3292017|Z3292017]]==

'''Lab 3 Online Assessment'''

''Question 1: Difference between post fertilisation age and gestational age''

Post fertilisation age (embryonic age) is dated at fertilisation of the egg which is approximately 2 weeks after the gestational age. This however is far less easy to determine than the gestational age as they calculate the time of ovulation as the oocyte is normally fertilised within the 12 hour period after ovulation.

Gestational age is the date of the beginning of the last normal menstrual period and is clinically more commonly used as it is a much easier method to calculate. Notably, the crown-rump length of the fetus along with the head and femur length are later used to confirm the estimated age of the fetus.

[http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00005-9--s0050&isbn=978-1-4377-2002-0&uniqId=351438666-2#4-u1.0-B978-1-4377-2002-0..00005-9--s0075| Estimation of gestational and embryonic age]

''Question 2: 3 different types of tissues formed from somites''

Ventromedially, the somite differentiates into the sclerotome which forms the vertebrae and the ribs. Studies have shown that Pax-1 is essential for the ventral sclerotome differentiation. The sclerotome differentiates into the vertebrae and ribs through bone formation. [http://www.ncbi.nlm.nih.gov/pubmed/8026324 Role of Pax-1 in skeleton development]. This is primarily initiated with mesenchymal cells which assists the formation of the pre-cartilage mass via chrondrocytes and subsequently cartilage formation. Bone then develops through the replacement of cartilaginous tissue with bone tissue. [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00014-X&isbn=978-1-4377-2002-0&uniqId=351438666-4 Development of bone and cartilage]

Dorsolaterally, the somite first differentiates into the dermomyotome which then creates 2 regions. The myotome region forms primordial muscle cells (myoblasts) and the dermatome region forms the fibroblasts (dermis). [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00015-1&isbn=978-1-4377-2002-0&uniqId=351438666-4#4-u1.0-B978-1-4377-2002-0..00015-1 Development of Muscle]

Dermatome along with Neurotrophin-3 assists with the early formation of the dermis. [http://www.ncbi.nlm.nih.gov/pubmed/7671821 Role of Neurotrophin-3] The dermal papillae consist mainly of fibroblasts and is located close to the epidermis. It contains both elastin and collagen fibres (produced by fibroblasts) with the elastin fibres perpendicular to the surface of the skin. The reticular dermis accounts for the majority of the dermis with multidirectional elastin and collagen fibres. Notably, in the dermal papillae, a plexus consisting of numerous blood vessels are found but do not penetrate into the epidermis. Some nerves within this region do penetrate through to the epidermis via free nerve endings which are linked to nerve corpuscles, such as Meissner's plexus. [http://www.skin-science.com/_int/_en/topic/topic_sousrub.aspx?tc=SKIN_SCIENCE_ROOT%5EAN_ORGAN_REVEALED%5ETHE_DERMIS&cur=THE_DERMIS Dermis formation]

Myotomes are separated into [http://embryology.med.unsw.edu.au/embryology/index.php?title=Musculoskeletal_System_-_Muscle_Development#Myotome epaxial muscles and hypaxial muscles] via primordial muscle cells . The epaxial muscles form the skeletal muscles dorsal to the vertebral column known as the erector spinae muscles. The hypaxial muscles form the ventral skeletal muscles which contribute to the lung and limb formation. The skeletal muscle fiber is long, cylindrical and multinucleated, with peripherally located nuclei.

==Lab 4 - [[User:Z3292017|Z3292017]]==

'''Lab 4 Online Assessment'''

''Question 1: 2 invasive prenatal diagnostic techniques related to the placenta:''

1. Amniocentesis:

A relatively common yet invasive procedure normally conducted between weeks 15-18 of gestation. A 22 gauge needle is inserted through the anterior abdominal and uterine walls (around the region of the umbilicus) of the mother into the amniotic cavity. Of the approximate 200mL volume that the mother is carrying at this early stage of pregnancy, only 15-20mL can be withdrawn safely. There is usually little risk when performing this procedure as an ultrasonography can be used concurrently to outline the fetal and placental position.

Amniocentesis is a procedure used to determine many genetic disorders such as Down Syndrome and also neural tube defects such as spina bifida cystica. [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00006-0--s0100&isbn=978-1-4377-2002-0&uniqId=352651422-2#4-u1.0-B978-1-4377-2002-0..00006-0--s0110| Amniocentesis - The Developing Human]

2. Chorionic Villus Sampling:

Trophoblastic tissue biopsies between 5-20 mg can be obtained through inserting a needle through the abdominal and uterine walls of the mother into the uterine cavity. This can also be completed transcervically using a polyethylene catheter through the cervix to obtain a chorionic villus sample. There is a slightly greater risk of miscarriage after this procedure has been performed when compared to amniocentesis (of around 1%).

Chorionic villus sampling is a procedure used to detect chromosomal abnormalities and also X linked disorders. The benefit of CVS over amniocentesis is that it can be performed between the 10th-12th week of gestation and thus giving an earlier diagnosis. [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00006-0--s0100&isbn=978-1-4377-2002-0&uniqId=352651422-2#4-u1.0-B978-1-4377-2002-0..00006-0--s0125| Chorionic Villus Sampling - The Developing Human]

''Question 2: Paper using cord stem cell therapeutically discussion of findings:''

Lim JY, Jeong CH, Jun JA, Kim SM, Ryu CH, Hou Y, Oh W, Chang JW, Jeun SS '''Therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of cerebral ischemia''' Stem Cell Res Ther. 2011; 2(5): 38 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3308035/?tool=pubmed| PMID: 21939558]

In this paper, the researchers investigated the effects of therapeutic potential of mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of stroke. Following this, the researchers then investigated whether the mesenchymal stem cells could enter and survive in the brain, and their potential to improve post stroke functional recovery. Mesenchymal stem cells (MSC) are a promising therapeutic strategy for the treatment of stroke due to their high proliferative capacity and also that they can be easily obtained.

The mesenchymal stem cells were injected intrathecally in some rats and intravenously in the others three days after Middle Coronary Artery Occlusion (MCAO) using isoflurane anesthesia. A 1cm incision was made over L3-L5 spinous processes and a neonatal lumbar puncture needed (25 gauge) was inserted into the spinal canal. MSCs (1 × 10^6) was diluted with 20 μl PBS being injected into the CSF over 30 seconds. Intravenously, MSCs (1 × 10^6) was diluted with 700 μl PBS were injected slowly for five minutes via an intravenous cannula situated in the tail vein. The presence and survival of the MSCs in the brain tissue was examined by immunohistochemistry. The rats were examined by their recovery of coordination of movement using both the Rotarod test and the adhesive removal test after the 1st, 2nd, 3rd and 4th week of stroke.

The results indicated that the MSC intrathecally receiving rats had an increased level of migrated cells to the ischemic area compared to the intravenous administration of MSCs. Additionally, many of the cells were expressing the mature neural lineage markers. Overall, the intrathecal administration of MSCs were more effective in reducing ischemic damage, yet proved to be similar to intravenous administration in promoting neurological recovery.

This study thus indicated a potential treatment for cerebral ischemia or neurodengerative disorders due to its ability to recover ischemic damaged tissue.

== Lab 7 ==

'''Lab 7 Online Assessment'''

''Question 1''

''(a) Definition of muscle satellite cell''

A muscle satellite cell is a quiescent mononucleated cell, which respond to injury by proliferating to form regenerated muscle and additional satellite cells, found between the basement membrane of specialised muscle fibres. [http://www.ncbi.nlm.nih.gov/pubmed/12757751| Muscle Satellite Cell PMID: 12757751]

''(b) Two examples of when satellite cells are activated''

Satellite cells are employed for skeletal muscle trauma and also disease.

* Muscle injury: When muscle injury occurs, the satellite cells are activated and will either form multinucleated myotubes to assist with muscle regeneration, or will form additional quiescent satellite cells in order to assist with more [http://www.ncbi.nlm.nih.gov/pubmed?term=The%20muscle%20satellite%20cell%20at%2050%3A%20the%20formative%20years| muscle regeneration]. Sambasivan et al. indicated in their 1993 study that other cells with regenerative potential depend on the satellite cell presence especially the Pax7 expressing satellite cells. [http://dev.biologists.org.wwwproxy0.library.unsw.edu.au/content/138/17/3647| Pax7-expressing satellite cells]

* Muscle disease: Research has shown that congenital myopathies such as Duchenne Muscular Dystrophy lead to a greater number of satellite cells than in normal muscle cells. Notably, the regenerative capacity of, for example Duchenne Muscular Dystrophy, is limited due to the severity and continuation of the disease. [http://genesdev.cshlp.org.wwwproxy0.library.unsw.edu.au/content/20/13/1692| Muscle stem cells in development, regeneration, and disease]

''Question 2: 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''

Spinal cord injury will result in partial or complete paralysis of the muscle innervation at or below the trauma level of the spinal cord resulting in atrophy. Some studies have noted that a some paralysed muscles due to spinal cord injury have an increase in force per cross sectional area of the muscle compared to normal in an attempt to maintains the muscle's normal strength. However, it is also important to note, the muscle cross sectional area significantly decreased. Due to the decrease in muscle, the study also indicated that there were increased levels of connective tissues and fat - thought to transfer more of the force to the tendon. Importantly, in chronic muscle denervation (greater than 50% of muscle size loss), the strength of the muscle (if there was any at all) has seriously deteriorated. [http://www.ibib.waw.pl/bbe/bbefulltext/bbe_25_3_039_ft.pdf| Muscle Atrophy after Human Spinal Cord Injury]

After a spinal cord injury the muscle fibre type pattern changes from a mix of type I and type II to predominantly type II fast glycolytic fibres. This is thought be an explanation of the quick muscle fatigue noted in rehabilitation. Notably, Burnham et al. discovered that the muscle fibre type change occurs in stages rather than an immediate effect and thus opens the door to more research to prevent the transformation of the muscle types from occurring, which is inidcated to be done within the first week or two following spinal cord injury. [http://www.ncbi.nlm.nih.gov/pubmed/9044514| Skeletal muscle fibre type transformation following spinal cord injury]

==Lab 8==

'''Lab 8 Online Assessment'''

'''Vision'''

The photo at the top of your page is a great choice and makes the site that much more appealing. The only suggestion I would have here is to potentially minimise the photo as it makes the contents section to the left of it hard to read. Your introduction is clear and concise and gives a good description of the eye. A slight adjustment I would make is perhaps to make it slightly longer giving a brief discussion about what is to be discussed on this page. Included in your introduction you have the anatomy of the eye. Firstly, would it be appropriate to include the histology as well, as it appears further down the page you discuss the cells, so perhaps if you gave a brief histological overview that could make the sections below easier for the reader to comprehend. I would probably add to that that if you were to include histology, to put the anatomy and histology into a new section just so it doesn’t clutter the introduction.

Your history, although I’m aware it ins’t finished, would read better if it were in a table and would also bring some more colour to the page. I’m assuming this will come when you finish this section, but it would be wise to include updated examples as well in order to show an adequate progression of the history.

The development section appears to be very thorough which is fantastic. It is rather clear that you have put a lot of research and time into this section. The introduction you have there is well written and again concise which is great. Additionally I like your use of photos just below it to further your explanation and also to break up the text. In regards to your photos, I would suggest perhaps a better description of them and to make sure you include where you got the photo from. If there were an explanation of the photo in simplistic terms, then I think the photos would be really beneficial.

The optic nerve section is well written but it appears to lack references?? In the first 3 paragraphs there are only 2 references. I would probably suggest that this information is backed up by additional sources as well. Also, with your hand drawn pictures (which are good), I would suggest an explanation on them when you open the picture up in another window. Your paragraph describing the 2 pictures, I would probably recommend that it become sintegrated within the text i.e. when you are talking about that part of it then include it there. I just think it would make it flow better that way – like you have done with figure 3.

The retina is good and well set out with pictures. However I noticed that you have used the exact references as before (3, 4)?? It would be really advisable to include many more references than what is listed. The same applies to the images as I said above, but good integration!

The ciliary body appears to be well researched and referenced. From the iris down there appears to be a lack of new references and also looks rather bland - so here I would suggest including additional photos from journal articles you have used. Also, it seems rather brief, I’m wondering whether there is more information about the embryological processes that could be included?

The current research is a good start, but there isn’t much of an explanation of the photo that is included and brief discussion of the research should probably be included. Are there additional research projects to include as well?

Finally, your references ar good but short. The fisrt 2 need to be put in the appropriate format. I would definitely suggest including many more references in order to make your information listed more valid.

'''Somatosensory development'''

I really like your introduction, I think that is is really informative and gives the reader a much clearer understanding of what this topic is about. Your references here need to be included in the reference section below but it appears that you have a good amount of references for the points depicted. At the end of the first paragraph it discusses a picture of the general organisation however there is not one there?? Also the inclusion of a picture would be agreat idea not only to further our understanding but also to break up the text and make it more appealing.

In your history of discoveries section I would probably recommend putting this in a colourful table, again to rbeak up the text, and also to make it easier to read. I would probably suggest here that you include a greater progression of discoveries to show the change of thinking over time. Note to also inlduce the appropriate referencing as shown in previous lab classes.

The central somatosensory differentiation is very expansive and informative. I would assume that you have put a lot of research into this section. Note that you have used pretty well the same references over and over. I would suggest that you include additional references to back up those statements as well. If those couple of references were the only ones saying that information, then I would suggest further researching to ensure that other journal articles don’t contradict this. The image is good and appears to show a good somatosensory pathway, however I would make the font bigger, so that it would not be imperative to enlarge the photo to read what is there. The picture has a discription when it is enlarged which is good, but I think it would also be appropriate to put the correct student information for the referencing.

In the Touch part, I noted that almost none of the text is refenced, which essentially makes the information listen invalid, so I would look into finding appropriate references here. Also, this section seems a bit dull with no pictures. Perhaps histological photos could be included here? I know we studied them in histology and this would make the section more interesting and also compliment the information stated. I would also suggest that those subheadings you don’t want in bold, you list in italic with two ‘ ‘ in order to separate it from the text below..

The Pain section probably needs to be set out better by using dot points? It appears that you have provided some excellent information but it is also important to put the references included with the reference section below. A photo here might be nice, perhaps of the different fibres if this can be found?

The Hot/Cold section is better set out and I like the appropriate referencing here. However, it appears that you are re-using the same references, so I would suggest some more research be done here to compliment your other references. It is better set out, however I would suggest some photos to be included if at all appropriate and can be found.

Pressure is similar to the pain section in the sense that the references really need to be put in the referencing section. It would also be advisable that you split the first paragraph up as it is rather long and not very appealing for one to read.

Current research section is good and concise. I like the use of the picture there, and I like the description that you have when you enlarge the picture. Is there any other current research happening now?

Finally, I would suggest adding more information outlining the development of these areas as I believe this to have been limited across the majority of sections. Although you are providing good reaseach and information describing these sections, as this is am embryology course, I would see it as appropriate that some sort of developmental progression is included – or if this is not known as of yet, for that to be stated. I would also highly recommend that you include a detailed glossary of words, as this is rather incomplete.

'''Taste development'''

The introduction section is very informative and I like the picture included discussing the 5 basic tastes which is interesting to read. I really enjoy your descriptions of bitter and sweet and find it interesting to read. I like the research you included in this section but I believe this needs to be referenced. Currently in the introduction you have only 1 references, so I would suggest that you find more to further validate your information (note that there are no references in the first paragraph). I like in your picture that you included a description. The cell biology section I would probably put in its own section with = = to break up the contend displayed. In this section it is clear that this has been researched however there have been no references listed at all here.

The taste map section has clearly been well researched yet poorly referenced. It would be interesting to look at if possible a progression of the understanding of the taste map. In the picture of the tongue, I would suggest that it has a better description on the enlarged image. However, some of this text is rather hard to read, such as the descriptions of the first and second order neurons. As you have included terms in there which would be foreign to most people, I would try to include either a picture to show exactly where these parts are such as the NTS which can give the reader a better understanding of what you’re saying. Note that you say things like “copious scientific conjecture surrounds…” however there is no references here! This section is well researched which is great, but I would really consider putting it into slightly easier terms to better comprehension.

In the cortical areas section, a similar approach applies: when describing locations of things such as the I/fO, you should really include a clear diagram as to where all of these are. I can see you included the section of the brain however don’t see it as too informative so a better description there would be appropriate. I would also note that you are repeating your references again, and it would be advisable that you find alternative information to include as well.

The timeline section is very informative and really stands out. I’m assuming you will be including the photos later this week. This is well written and gives a truly informative description of the embryological changes that occur. It will look much better and be better to understand once the photos have been included. Note that you have used the same references pretty well the whole time in this section. Although that paper may have a lot of information about what you are needing to talk about, I would also encourage you to research more papers in order to compliment the information you have listed.

The history of discoveries section is well set out and clear and concise. In some areas I would suggest a brief descripton of what you have written such as “PKD2L”, and also make sure you include the appropriate references as all I can see currently it numbers.

In the adult tongue and taste bud section, is this also what the tongue looks like from week 15? If not what changes occurs for it to form into what you have described as the adult tongue and what enhances these changes? This section is informative however it is really lacking references. The taste bud picture you have is quite good, but is that also what the taste bud looks like at 15 weeks?

The abnormalities section is really interesting and is rather enjoyable to read. Are they the only abnormalities that can happen to the tongue? How about environmental? Does alcohol, smoking or drugs affects its development of either the tongue or the taste buds? Additonally, your current research is very thorough and interesting. In regards to the photos you have there, I would make sure that they are set out appropriately, with the information that this is a student project.

Finally, the glossary needs to be highlighted to make it stand out and more words need to be included. Note that in your references, reference 5 can not be accessible, so make sure you fix that up. Overall, it was interesting to read and I enjoyed the display of photos that were also included!

'''Olfaction'''

Your introduction is good and concise giving a simple understanding of the olfactory system. Here I would suggest that you include what you’re about to discuss on the page. I also think you should include some references and maybe a photo in this section. The references to show that this information has been researched and the photo to break up the text and give the reader a simple understanding of the olfactory system.

The history of discovery section is clearly well researched and is well set out. However, I would suggest that you include brief descriptions of what has been described such as the Vomeronasal organ or the Nobel Prize which will further enhance the readers understanding. You have a good use of references there as well. In the picture that was included in this section, I would provide a more indepth description of what is drawn i.e. what the ectoderm is etc.

The timeline of developmental process is really well set out and easy to read. I would just make sure that every new point you include, you put it with a references as some of your points are not referenced at all and you need to be careful of that! I would also suggest that you put it in appropriate bullet points using the star key on your keyboard, that way it can be set out a bit better. Also, at the end of week 8, does this mean the olfactory system is complete by then? If so, then I would suggest you state that in that final week, if not, then what other small changes occur throughout the duration of the pregnancy? Also note that week 6 – 8 the references are either limited or not there, so I would recommend putting them in.

The anatomy of the olfactory system and the normal function are limited in information but also have only one reference between them. The images attached should really have more of a description when the picture is enlarged to give the reader a better understanding of what you’re talking about. Such as: diagram of olfactory bulb- what does it do and where is it located?

The abnormality section is rather indepth for 2 conditions, are there any other factors that come into play in regards to olfactory defects? Such as environmental? The Kallmann’s syndrome is really indepth and describes the clinical features, diagnosis and treatment, could this also be implementd with the Choanal atresia? Or are the same techniques used there? Also, be careful when you use shortening of words such as OB, you provided the HH in brackets first, so I would suggest the same is done with the olfactory bulb just to prevent confusion. I like your use of both images and give s a simple but good explanation of what you have been discussing (and also breaks up the text!). I like how you have provided a good description in the enlarged picture and it makes it easier for the reader to understand.

The current research section really shows that you have put a lot of effort in for this section. However, at the beginning of each new research you state either a study or a paper with a link, perhaps use the name of the paper and who wrote it and use that as the link instead. It is really interesting and I rather enjoyed reading it, however, if possible I would add some more photos just to break up the text. Your glossary is good and well set out and the information displayed is quite easy to understand, however I would consider adding to this section as there were some other words throughout the page which were in need of a slight description. You have an excellent use of references which is great, but I would have another look at reference 11 as there is no text, only an arrow.

'''Abnormal vision'''

Your introduction is rather succinct which I like but I would encourage you to put references in this section. I would also suggest that you split it into 2 paragraphs to make it easier to read. Perhaps maybe you could put a photo of a normal eye in this section to show what it should look like, and then throughout the paper as you discuss the abnormal developments, you it could give the reader a better understanding as to how exactly this has altered the eye using the comparison.

The Normal eye development section is good as it provides a way for the reader to compare the differences in progression when referring to the different abnormalities listed below. However I would possibly suggest this to be put in a table, with perhaps a sentence at the top saying something along the lines of in order to fully comprehend abnormal development, an understanding of normal eye development is important - that way the reader can understand why you put this section in. I would also suggest a picture here.

The abnormal lens development section is clearly very well researched with a wide range of references. I like how you have separated the development in to the different sections of the eye as this can give a more thorough insight into these abnormalities. I think this section has been well written, and the only suggestion I would have would be in regards to the photo presented. Perhaps include some arrows to point at the sections you’re talking about and discuss what the nuclear area of the lens is?

The anormal corneal development and the abnormal retinal development are very descriptive and well referenced. I would perhaps look at moving the photo in the corneal development up a bit more and again I would provide more of a description of what is shown. If possible, I would try and make the abnormal retinal photo bigger.

Ocular manifestations is a bit confusing as im not sure if it’s a new heaing all together of if it is supposed to be part of the broad category of abnormalities. Your genetic section is well researched, I would just be careful in referencing the same paper too many times (25 is listed 5 times in this section) and perhaps try and find some other papers which compliment this research? I would probably put your reseach timeline at the bottome and include all of the treatment and clinical manifestation flowing on from each other. Note that in the research timeline, this is purely from one source, reference 26, and I would advise that you find alternative sources as well – im sure there would be individual research papers for each new date??

The anophthalmia section im assuming is still part of genetic abnormalities and I would recommend starting with the genes which are affected – to create a flow on effect. Other than that it is well references and easy to read. In regards to your photo I would have a description of what the photo is about in the enlarged view to assist with the readers comprehension. Also, at what point can these abnormalities be detected in the womb – either from an ultrasound or from sampling of the genes or something - and does this have an affect on whether the mother keeps the child or not? I think the environmental causes of abnormalities are good and I would suggest that you add photos here to break up the text and also to give us an understanding of what happens.

Finally, your glossary needs a fair few more words in there as to help with our understanding. You have many references which is great, however take a loot at 46 – 49 – they all seem to be the same? It would be appropriate to merge them into one reference.

===Lab 9 ===

'''1. 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.'''

<pubmed>21490060</pubmed>

This research paper wanted to determine if Cdk4 has a role in embryonic pancreas development. The study required embryos being harvested from mice (Cdk4+/+, Cdk4–/– and Cdk4R24C) 1 hour after the discovery of the vaginal plug. The results indicated that Cdk4 is needed for growth and morphogenesis of the developing pancreas. Cdk4 deficiency decreases the size of the pancreas due to diminished mesenchyme development and less Pdx1+ cells. The results allude to the fact that Cdk4 promotes the Beta cell growth from the signalling transcription factor E2f1 to assist in the proliferation of Ngn3+endocrine precursors. Cdk4 thus is seen as an imperative regulator of the early developmental stages of the pancreas which regulates the growth of the endocrine precursors and pancreatic progenitors.

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

The teeth development necessitates the epithelial/ mesenchymal interaction between the ectoderm of the first pharyngeal arch along with ectomesenchymal cells of the neural crest . The tooth bud is the name given to the collection of cells which will later form a tooth <ref><pubmed>12615136</pubmed></ref>. There are 3 sections which contribute to the [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00019-9&isbn=978-1-4377-2002-0&uniqId=369704599-2#4-u1.0-B978-1-4377-2002-0..00019-9--s0055| developing teeth]:
# The enamel organ: The cells of the inner enamel epithelium of the enamel organ form the ameloblasts which differentiates and produces the enamel.
# The dental papilla: This is formed by the neural crest and cells from an unknown origin <ref><pubmed>21425080</pubmed></ref>. These cells develop into odontoblasts (or dentin forming cells). The mesenchymal cells contribute to the formation of the tooth pulp.
# The dental follicle: This produces 3 different cells. Cementoblasts create the cementum of the tooth. The osteoblasts create the alveolar bone around the tooth roots. Finally, the fibroblasts form the periodontal ligaments which attach the teeth to the alveolar bone.

Therefore, the ectoderm, neural crest and mesoderm all contribute to the development of the tooth.

===Lab 11 ===

<pubmed>22495829</pubmed>

In this research article, long term expandable neuro-epithelial like stem cells (It-NES) produced from the adult human fibroblast derived iPSCs were transplanted into the areas of stroke in mice and rat brains. Human induced pluripotent stem cells were produced and then were transformed into neuroepithelial like stem cells. The mice and rats incurred a middle cerebral artery occlusion and a week later, the human induced pluripotent stem cells were transplanted intracranially highlighted with a green fluorescent protein. 9 weeks following the transplant of the stem cells, the mice and rats were injected with 2% fluro-gold. Subsequently behaviourable tests along with cell counting and VEGF immunoreactivity took place to determine the effect of the induced pluripotent stem cells.

The results indicated that the transplanted neuro-epithelial like stem cells lead to an improved recovery of the motor deficit. The noted neuronal markers in the graft area at 10 week post transplantation, however they believe that recovery occurred much earlier on due to the progress they saw. This could be due to additional mechanisms working with the neuronal replacement. Notably, behavioural recovery was increased in both the mice and rats regardless if they had been transplanted with the neuroepithelial like stem cells.

The researchers believe that the raised levels of VEGF in the animals with the transplants were found to be important for minimising the inflammation and the neovascularisation in the peri infarct region. The transplanted cells also showed characteristic neuronal morphologies and had markers which showed that they had differentiated into different neuron subtypes. Additionally, through the electrophysical data, the induced pluripotent stem cells indicated they were able to differentiate into functional neurons creating normal connections with the host brain, along with synaptic input from the neurons of the host brain. After approximately 5 months, the transplanted cells showed electrophysiological qualities of normal mature neurons. This article was the first of its kind to show that induced pluripotent stem cells are able to replace sections of a stroke damaged brain.

===References===
<references/>

User:Z3292017

2012-10-16T21:53:01Z

Z3292017: /* Lab 11 */

=='''Lab Attendance'''==

Lab 1 - [[User:Z3292017|Z3292017]] 10:15, 25 July 2012 (EST)

Lab 2 - [[User:Z3292017|Z3292017]] 10:17, 1 July 2012 (EST)

Lab 3 - [[User:Z3292017|Z3292017]] 10:13, 8 August 2012 (EST)

Lab 4 - [[User:Z3292017|Z3292017]] 11:23, 15 August 2012 (EST)

Lab 5 - [[User:Z3292017|Z3292017]] 10:34, 22 August 2012 (EST)

Lab 6 - [[User:Z3292017|Z3292017]] 11:31, 29 August 2012 (EST)

Lab 7 - [[User:Z3292017|Z3292017]] 10:14, 12 September 2012 (EST)

Lab 8 - [[User:Z3292017|Z3292017]] 10:13, 19 September 2012 (EST)

Lab 9 - [[User:Z3292017|Z3292017]] 11:11, 26 September 2012 (EST)

Lab 10 - [[User:Z3292017|Z3292017]] 11:06, 3 October 2012 (EST)

Lab 11 - [[User:Z3292017|Z3292017]] 10:05, 10 October 2012 (EST)

==Lab 1 - [[User:Z3292017|Z3292017]]==

'''Lab 1 Online Assessment'''

''Question 1: Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique:''

The origin of IVF can be dated from the late 19th Century where embryo transplantation in rabbits was discovered by Walter Heape. The development of IVF was due to a cascade of events during the 20th century. Pincus and Enzmann from Harvard University suggested the possibility that mammalian eggs are able to develop normally in vitro in 1934. In 1948 Menken and Rock exposed 138 oocytes to spermatozoa in vitro. In 1959, Change was able to provide evidence for IVF by fertilising rabbit eggs with capicated sperm and thus achieve birth. From 1965 Robert Edwards attempted to fertilise human oocytes in vitro. In 1968 Edwards successfully fertilised a human egg using a human culture media he developed. Finally after years of research and failed attempts, the first test tube baby was born in 1978.
Robert Edwards was awarded the Nobel Prize in Physiology and Medicine in 2010 due to his immense development and contribution of IVF.

'''References'''
<references/>
#http://www.ivf-worldwide.com/ivf-history.html
#http://en.wikipedia.org/wiki/In_vitro_fertilisation
#http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/

''Question 2: Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings:''

Cleavage speed and implantation potential of early cleavage embryos in IVF or ICSI cycles by Lee, Lin and Hwu (July, 2012) attempted to determine the correlation of early embryo cleavage, its speed and the potential implantation rates for IVF. Their definition of early cleavage was embryonic mitosis occurring 25-27 hours after insemination. The embryos’ (day 3) cleavage speed was assessed and rated into 3 groups: rapid (more than 9 cells), normal (7-8 cells) and slow (less than 7 cells) along with their morphological quality being either good or poor. Normal fertilisation was determined by the presence of 2 nuclei and 2 polar bodies. 25-27 hours after IVF an early cleavage examination took place to determine which embryos had already cleaved. They embryos were then examined for their quality from 66-68 hours after IVF.

Early cleavage emrbyos developed normally in comparison to non early cleavage embryos. Notably, the early cleavage embryos produced a greater amount of “good quality” embryos and subsequently the implantation rate was sufficiently greater with early cleavage embryos. This finding is of great importance as embryo morphology is the most important tool to select the best embryo to transfer andthus increase the rates of implantation, pregnancy and live birth.

'''References'''

Lee MJ, Lee RK, Lin MH, Hwu YM '''Cleavage speed and implantation potential of early-cleavage embryos in IVF or ICSI cycles.''' J Assist Reprod Genet. 2012 Jul 25 PMID: 22825967

==Lab 2 - [[User:Z3292017|Z3292017]]==

'''Lab 2 Online Assessment'''

''Question 1: Image from journal source''

[[File:zygote.jpg]]

Zygotes showing different distribution of NPB in the 2PN and different PB alignment <ref>Alessia Nicoli, Francesco Capodanno, Lucia Moscato, Ilaria Rondini, Maria T Villani, Antonella Tuzio, and Giovanni B La Sala (2010) '''Analysis of pronuclear zygote configurations in 459 clinical pregnancies obtained with assisted reproductive technique procedures''' Department of Obstetrics and Gynecology, Arcispedale Santa Maria Nuova, Reprod Biol Endocrinol. 2010; 8: 77. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902489/?tool=pubmed NCBI]</ref>

===Reference===

<references/>

''Question 2: Identify a protein associated with the implantation process, including a brief description of the protein's role''

Proprotein convertase 6 (PC6) is a necessary regulatory molecule for embryo implantation which generates bioactive proteins such as growth factors, peptide hormones and adhesion molecules. It is produced in the uterine stromal cells in particular at the embryo attachment site throughout early pregnancy in mice. In order for implantation to occur, the uterus ungergoes morphological and physiological changes, one being differentiation of endometrial stromal cells.

Studies have shown that PC6 mRNA is upregulated in particularly at the site of embryo attachment in the mouse uterus, being predominantly at the antimesometrial pole undergoing decidualisation. These results imply that PC6 is associated with decidualisation. From this study, the researchers were able to determine that endometrial PC6 is imperative for maternal stromal decidual response for an implanting embryo during the time of implantation. They discovered that endometrial PC6 is produced explicitly in decidual cells (the vascular and cellular changes in a uterus in preparation for pregnancy) and is not found in other cells as well as the embryo. Similarly, they noted that inhibition of the production of PC6 early on (around day 3.5) using anti-PC6 MO blocked the decidualisation and thus impeded implantation. Notably, PC6 is produced in the late secretory phase of the menstrual cycle in preparation for implantation.

===Reference===

Guiying Nie, Ying Li, Min Wang, Yi Xun Liu, Jock K. Findlay and Lois A. Salamonsen '''Inhibiting Uterine PC6 Blocks Embryo Implantation: An Obligatory Role for a Proprotein Convertase in Fertility''' Biology of Reproduction April 1, 2005 vol. 72 no. 4 1029-1036. [http://www.biolreprod.org/content/72/4/1029.long Biology of Reproduction]

==Lab 3 - [[User:Z3292017|Z3292017]]==

'''Lab 3 Online Assessment'''

''Question 1: Difference between post fertilisation age and gestational age''

Post fertilisation age (embryonic age) is dated at fertilisation of the egg which is approximately 2 weeks after the gestational age. This however is far less easy to determine than the gestational age as they calculate the time of ovulation as the oocyte is normally fertilised within the 12 hour period after ovulation.

Gestational age is the date of the beginning of the last normal menstrual period and is clinically more commonly used as it is a much easier method to calculate. Notably, the crown-rump length of the fetus along with the head and femur length are later used to confirm the estimated age of the fetus.

[http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00005-9--s0050&isbn=978-1-4377-2002-0&uniqId=351438666-2#4-u1.0-B978-1-4377-2002-0..00005-9--s0075| Estimation of gestational and embryonic age]

''Question 2: 3 different types of tissues formed from somites''

Ventromedially, the somite differentiates into the sclerotome which forms the vertebrae and the ribs. Studies have shown that Pax-1 is essential for the ventral sclerotome differentiation. The sclerotome differentiates into the vertebrae and ribs through bone formation. [http://www.ncbi.nlm.nih.gov/pubmed/8026324 Role of Pax-1 in skeleton development]. This is primarily initiated with mesenchymal cells which assists the formation of the pre-cartilage mass via chrondrocytes and subsequently cartilage formation. Bone then develops through the replacement of cartilaginous tissue with bone tissue. [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00014-X&isbn=978-1-4377-2002-0&uniqId=351438666-4 Development of bone and cartilage]

Dorsolaterally, the somite first differentiates into the dermomyotome which then creates 2 regions. The myotome region forms primordial muscle cells (myoblasts) and the dermatome region forms the fibroblasts (dermis). [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00015-1&isbn=978-1-4377-2002-0&uniqId=351438666-4#4-u1.0-B978-1-4377-2002-0..00015-1 Development of Muscle]

Dermatome along with Neurotrophin-3 assists with the early formation of the dermis. [http://www.ncbi.nlm.nih.gov/pubmed/7671821 Role of Neurotrophin-3] The dermal papillae consist mainly of fibroblasts and is located close to the epidermis. It contains both elastin and collagen fibres (produced by fibroblasts) with the elastin fibres perpendicular to the surface of the skin. The reticular dermis accounts for the majority of the dermis with multidirectional elastin and collagen fibres. Notably, in the dermal papillae, a plexus consisting of numerous blood vessels are found but do not penetrate into the epidermis. Some nerves within this region do penetrate through to the epidermis via free nerve endings which are linked to nerve corpuscles, such as Meissner's plexus. [http://www.skin-science.com/_int/_en/topic/topic_sousrub.aspx?tc=SKIN_SCIENCE_ROOT%5EAN_ORGAN_REVEALED%5ETHE_DERMIS&cur=THE_DERMIS Dermis formation]

Myotomes are separated into [http://embryology.med.unsw.edu.au/embryology/index.php?title=Musculoskeletal_System_-_Muscle_Development#Myotome epaxial muscles and hypaxial muscles] via primordial muscle cells . The epaxial muscles form the skeletal muscles dorsal to the vertebral column known as the erector spinae muscles. The hypaxial muscles form the ventral skeletal muscles which contribute to the lung and limb formation. The skeletal muscle fiber is long, cylindrical and multinucleated, with peripherally located nuclei.

==Lab 4 - [[User:Z3292017|Z3292017]]==

'''Lab 4 Online Assessment'''

''Question 1: 2 invasive prenatal diagnostic techniques related to the placenta:''

1. Amniocentesis:

A relatively common yet invasive procedure normally conducted between weeks 15-18 of gestation. A 22 gauge needle is inserted through the anterior abdominal and uterine walls (around the region of the umbilicus) of the mother into the amniotic cavity. Of the approximate 200mL volume that the mother is carrying at this early stage of pregnancy, only 15-20mL can be withdrawn safely. There is usually little risk when performing this procedure as an ultrasonography can be used concurrently to outline the fetal and placental position.

Amniocentesis is a procedure used to determine many genetic disorders such as Down Syndrome and also neural tube defects such as spina bifida cystica. [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00006-0--s0100&isbn=978-1-4377-2002-0&uniqId=352651422-2#4-u1.0-B978-1-4377-2002-0..00006-0--s0110| Amniocentesis - The Developing Human]

2. Chorionic Villus Sampling:

Trophoblastic tissue biopsies between 5-20 mg can be obtained through inserting a needle through the abdominal and uterine walls of the mother into the uterine cavity. This can also be completed transcervically using a polyethylene catheter through the cervix to obtain a chorionic villus sample. There is a slightly greater risk of miscarriage after this procedure has been performed when compared to amniocentesis (of around 1%).

Chorionic villus sampling is a procedure used to detect chromosomal abnormalities and also X linked disorders. The benefit of CVS over amniocentesis is that it can be performed between the 10th-12th week of gestation and thus giving an earlier diagnosis. [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00006-0--s0100&isbn=978-1-4377-2002-0&uniqId=352651422-2#4-u1.0-B978-1-4377-2002-0..00006-0--s0125| Chorionic Villus Sampling - The Developing Human]

''Question 2: Paper using cord stem cell therapeutically discussion of findings:''

Lim JY, Jeong CH, Jun JA, Kim SM, Ryu CH, Hou Y, Oh W, Chang JW, Jeun SS '''Therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of cerebral ischemia''' Stem Cell Res Ther. 2011; 2(5): 38 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3308035/?tool=pubmed| PMID: 21939558]

In this paper, the researchers investigated the effects of therapeutic potential of mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of stroke. Following this, the researchers then investigated whether the mesenchymal stem cells could enter and survive in the brain, and their potential to improve post stroke functional recovery. Mesenchymal stem cells (MSC) are a promising therapeutic strategy for the treatment of stroke due to their high proliferative capacity and also that they can be easily obtained.

The mesenchymal stem cells were injected intrathecally in some rats and intravenously in the others three days after Middle Coronary Artery Occlusion (MCAO) using isoflurane anesthesia. A 1cm incision was made over L3-L5 spinous processes and a neonatal lumbar puncture needed (25 gauge) was inserted into the spinal canal. MSCs (1 × 10^6) was diluted with 20 μl PBS being injected into the CSF over 30 seconds. Intravenously, MSCs (1 × 10^6) was diluted with 700 μl PBS were injected slowly for five minutes via an intravenous cannula situated in the tail vein. The presence and survival of the MSCs in the brain tissue was examined by immunohistochemistry. The rats were examined by their recovery of coordination of movement using both the Rotarod test and the adhesive removal test after the 1st, 2nd, 3rd and 4th week of stroke.

The results indicated that the MSC intrathecally receiving rats had an increased level of migrated cells to the ischemic area compared to the intravenous administration of MSCs. Additionally, many of the cells were expressing the mature neural lineage markers. Overall, the intrathecal administration of MSCs were more effective in reducing ischemic damage, yet proved to be similar to intravenous administration in promoting neurological recovery.

This study thus indicated a potential treatment for cerebral ischemia or neurodengerative disorders due to its ability to recover ischemic damaged tissue.

== Lab 7 ==

'''Lab 7 Online Assessment'''

''Question 1''

''(a) Definition of muscle satellite cell''

A muscle satellite cell is a quiescent mononucleated cell, which respond to injury by proliferating to form regenerated muscle and additional satellite cells, found between the basement membrane of specialised muscle fibres. [http://www.ncbi.nlm.nih.gov/pubmed/12757751| Muscle Satellite Cell PMID: 12757751]

''(b) Two examples of when satellite cells are activated''

Satellite cells are employed for skeletal muscle trauma and also disease.

* Muscle injury: When muscle injury occurs, the satellite cells are activated and will either form multinucleated myotubes to assist with muscle regeneration, or will form additional quiescent satellite cells in order to assist with more [http://www.ncbi.nlm.nih.gov/pubmed?term=The%20muscle%20satellite%20cell%20at%2050%3A%20the%20formative%20years| muscle regeneration]. Sambasivan et al. indicated in their 1993 study that other cells with regenerative potential depend on the satellite cell presence especially the Pax7 expressing satellite cells. [http://dev.biologists.org.wwwproxy0.library.unsw.edu.au/content/138/17/3647| Pax7-expressing satellite cells]

* Muscle disease: Research has shown that congenital myopathies such as Duchenne Muscular Dystrophy lead to a greater number of satellite cells than in normal muscle cells. Notably, the regenerative capacity of, for example Duchenne Muscular Dystrophy, is limited due to the severity and continuation of the disease. [http://genesdev.cshlp.org.wwwproxy0.library.unsw.edu.au/content/20/13/1692| Muscle stem cells in development, regeneration, and disease]

''Question 2: 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''

Spinal cord injury will result in partial or complete paralysis of the muscle innervation at or below the trauma level of the spinal cord resulting in atrophy. Some studies have noted that a some paralysed muscles due to spinal cord injury have an increase in force per cross sectional area of the muscle compared to normal in an attempt to maintains the muscle's normal strength. However, it is also important to note, the muscle cross sectional area significantly decreased. Due to the decrease in muscle, the study also indicated that there were increased levels of connective tissues and fat - thought to transfer more of the force to the tendon. Importantly, in chronic muscle denervation (greater than 50% of muscle size loss), the strength of the muscle (if there was any at all) has seriously deteriorated. [http://www.ibib.waw.pl/bbe/bbefulltext/bbe_25_3_039_ft.pdf| Muscle Atrophy after Human Spinal Cord Injury]

After a spinal cord injury the muscle fibre type pattern changes from a mix of type I and type II to predominantly type II fast glycolytic fibres. This is thought be an explanation of the quick muscle fatigue noted in rehabilitation. Notably, Burnham et al. discovered that the muscle fibre type change occurs in stages rather than an immediate effect and thus opens the door to more research to prevent the transformation of the muscle types from occurring, which is inidcated to be done within the first week or two following spinal cord injury. [http://www.ncbi.nlm.nih.gov/pubmed/9044514| Skeletal muscle fibre type transformation following spinal cord injury]

==Lab 8==

'''Lab 8 Online Assessment'''

'''Vision'''

The photo at the top of your page is a great choice and makes the site that much more appealing. The only suggestion I would have here is to potentially minimise the photo as it makes the contents section to the left of it hard to read. Your introduction is clear and concise and gives a good description of the eye. A slight adjustment I would make is perhaps to make it slightly longer giving a brief discussion about what is to be discussed on this page. Included in your introduction you have the anatomy of the eye. Firstly, would it be appropriate to include the histology as well, as it appears further down the page you discuss the cells, so perhaps if you gave a brief histological overview that could make the sections below easier for the reader to comprehend. I would probably add to that that if you were to include histology, to put the anatomy and histology into a new section just so it doesn’t clutter the introduction.

Your history, although I’m aware it ins’t finished, would read better if it were in a table and would also bring some more colour to the page. I’m assuming this will come when you finish this section, but it would be wise to include updated examples as well in order to show an adequate progression of the history.

The development section appears to be very thorough which is fantastic. It is rather clear that you have put a lot of research and time into this section. The introduction you have there is well written and again concise which is great. Additionally I like your use of photos just below it to further your explanation and also to break up the text. In regards to your photos, I would suggest perhaps a better description of them and to make sure you include where you got the photo from. If there were an explanation of the photo in simplistic terms, then I think the photos would be really beneficial.

The optic nerve section is well written but it appears to lack references?? In the first 3 paragraphs there are only 2 references. I would probably suggest that this information is backed up by additional sources as well. Also, with your hand drawn pictures (which are good), I would suggest an explanation on them when you open the picture up in another window. Your paragraph describing the 2 pictures, I would probably recommend that it become sintegrated within the text i.e. when you are talking about that part of it then include it there. I just think it would make it flow better that way – like you have done with figure 3.

The retina is good and well set out with pictures. However I noticed that you have used the exact references as before (3, 4)?? It would be really advisable to include many more references than what is listed. The same applies to the images as I said above, but good integration!

The ciliary body appears to be well researched and referenced. From the iris down there appears to be a lack of new references and also looks rather bland - so here I would suggest including additional photos from journal articles you have used. Also, it seems rather brief, I’m wondering whether there is more information about the embryological processes that could be included?

The current research is a good start, but there isn’t much of an explanation of the photo that is included and brief discussion of the research should probably be included. Are there additional research projects to include as well?

Finally, your references ar good but short. The fisrt 2 need to be put in the appropriate format. I would definitely suggest including many more references in order to make your information listed more valid.

'''Somatosensory development'''

I really like your introduction, I think that is is really informative and gives the reader a much clearer understanding of what this topic is about. Your references here need to be included in the reference section below but it appears that you have a good amount of references for the points depicted. At the end of the first paragraph it discusses a picture of the general organisation however there is not one there?? Also the inclusion of a picture would be agreat idea not only to further our understanding but also to break up the text and make it more appealing.

In your history of discoveries section I would probably recommend putting this in a colourful table, again to rbeak up the text, and also to make it easier to read. I would probably suggest here that you include a greater progression of discoveries to show the change of thinking over time. Note to also inlduce the appropriate referencing as shown in previous lab classes.

The central somatosensory differentiation is very expansive and informative. I would assume that you have put a lot of research into this section. Note that you have used pretty well the same references over and over. I would suggest that you include additional references to back up those statements as well. If those couple of references were the only ones saying that information, then I would suggest further researching to ensure that other journal articles don’t contradict this. The image is good and appears to show a good somatosensory pathway, however I would make the font bigger, so that it would not be imperative to enlarge the photo to read what is there. The picture has a discription when it is enlarged which is good, but I think it would also be appropriate to put the correct student information for the referencing.

In the Touch part, I noted that almost none of the text is refenced, which essentially makes the information listen invalid, so I would look into finding appropriate references here. Also, this section seems a bit dull with no pictures. Perhaps histological photos could be included here? I know we studied them in histology and this would make the section more interesting and also compliment the information stated. I would also suggest that those subheadings you don’t want in bold, you list in italic with two ‘ ‘ in order to separate it from the text below..

The Pain section probably needs to be set out better by using dot points? It appears that you have provided some excellent information but it is also important to put the references included with the reference section below. A photo here might be nice, perhaps of the different fibres if this can be found?

The Hot/Cold section is better set out and I like the appropriate referencing here. However, it appears that you are re-using the same references, so I would suggest some more research be done here to compliment your other references. It is better set out, however I would suggest some photos to be included if at all appropriate and can be found.

Pressure is similar to the pain section in the sense that the references really need to be put in the referencing section. It would also be advisable that you split the first paragraph up as it is rather long and not very appealing for one to read.

Current research section is good and concise. I like the use of the picture there, and I like the description that you have when you enlarge the picture. Is there any other current research happening now?

Finally, I would suggest adding more information outlining the development of these areas as I believe this to have been limited across the majority of sections. Although you are providing good reaseach and information describing these sections, as this is am embryology course, I would see it as appropriate that some sort of developmental progression is included – or if this is not known as of yet, for that to be stated. I would also highly recommend that you include a detailed glossary of words, as this is rather incomplete.

'''Taste development'''

The introduction section is very informative and I like the picture included discussing the 5 basic tastes which is interesting to read. I really enjoy your descriptions of bitter and sweet and find it interesting to read. I like the research you included in this section but I believe this needs to be referenced. Currently in the introduction you have only 1 references, so I would suggest that you find more to further validate your information (note that there are no references in the first paragraph). I like in your picture that you included a description. The cell biology section I would probably put in its own section with = = to break up the contend displayed. In this section it is clear that this has been researched however there have been no references listed at all here.

The taste map section has clearly been well researched yet poorly referenced. It would be interesting to look at if possible a progression of the understanding of the taste map. In the picture of the tongue, I would suggest that it has a better description on the enlarged image. However, some of this text is rather hard to read, such as the descriptions of the first and second order neurons. As you have included terms in there which would be foreign to most people, I would try to include either a picture to show exactly where these parts are such as the NTS which can give the reader a better understanding of what you’re saying. Note that you say things like “copious scientific conjecture surrounds…” however there is no references here! This section is well researched which is great, but I would really consider putting it into slightly easier terms to better comprehension.

In the cortical areas section, a similar approach applies: when describing locations of things such as the I/fO, you should really include a clear diagram as to where all of these are. I can see you included the section of the brain however don’t see it as too informative so a better description there would be appropriate. I would also note that you are repeating your references again, and it would be advisable that you find alternative information to include as well.

The timeline section is very informative and really stands out. I’m assuming you will be including the photos later this week. This is well written and gives a truly informative description of the embryological changes that occur. It will look much better and be better to understand once the photos have been included. Note that you have used the same references pretty well the whole time in this section. Although that paper may have a lot of information about what you are needing to talk about, I would also encourage you to research more papers in order to compliment the information you have listed.

The history of discoveries section is well set out and clear and concise. In some areas I would suggest a brief descripton of what you have written such as “PKD2L”, and also make sure you include the appropriate references as all I can see currently it numbers.

In the adult tongue and taste bud section, is this also what the tongue looks like from week 15? If not what changes occurs for it to form into what you have described as the adult tongue and what enhances these changes? This section is informative however it is really lacking references. The taste bud picture you have is quite good, but is that also what the taste bud looks like at 15 weeks?

The abnormalities section is really interesting and is rather enjoyable to read. Are they the only abnormalities that can happen to the tongue? How about environmental? Does alcohol, smoking or drugs affects its development of either the tongue or the taste buds? Additonally, your current research is very thorough and interesting. In regards to the photos you have there, I would make sure that they are set out appropriately, with the information that this is a student project.

Finally, the glossary needs to be highlighted to make it stand out and more words need to be included. Note that in your references, reference 5 can not be accessible, so make sure you fix that up. Overall, it was interesting to read and I enjoyed the display of photos that were also included!

'''Olfaction'''

Your introduction is good and concise giving a simple understanding of the olfactory system. Here I would suggest that you include what you’re about to discuss on the page. I also think you should include some references and maybe a photo in this section. The references to show that this information has been researched and the photo to break up the text and give the reader a simple understanding of the olfactory system.

The history of discovery section is clearly well researched and is well set out. However, I would suggest that you include brief descriptions of what has been described such as the Vomeronasal organ or the Nobel Prize which will further enhance the readers understanding. You have a good use of references there as well. In the picture that was included in this section, I would provide a more indepth description of what is drawn i.e. what the ectoderm is etc.

The timeline of developmental process is really well set out and easy to read. I would just make sure that every new point you include, you put it with a references as some of your points are not referenced at all and you need to be careful of that! I would also suggest that you put it in appropriate bullet points using the star key on your keyboard, that way it can be set out a bit better. Also, at the end of week 8, does this mean the olfactory system is complete by then? If so, then I would suggest you state that in that final week, if not, then what other small changes occur throughout the duration of the pregnancy? Also note that week 6 – 8 the references are either limited or not there, so I would recommend putting them in.

The anatomy of the olfactory system and the normal function are limited in information but also have only one reference between them. The images attached should really have more of a description when the picture is enlarged to give the reader a better understanding of what you’re talking about. Such as: diagram of olfactory bulb- what does it do and where is it located?

The abnormality section is rather indepth for 2 conditions, are there any other factors that come into play in regards to olfactory defects? Such as environmental? The Kallmann’s syndrome is really indepth and describes the clinical features, diagnosis and treatment, could this also be implementd with the Choanal atresia? Or are the same techniques used there? Also, be careful when you use shortening of words such as OB, you provided the HH in brackets first, so I would suggest the same is done with the olfactory bulb just to prevent confusion. I like your use of both images and give s a simple but good explanation of what you have been discussing (and also breaks up the text!). I like how you have provided a good description in the enlarged picture and it makes it easier for the reader to understand.

The current research section really shows that you have put a lot of effort in for this section. However, at the beginning of each new research you state either a study or a paper with a link, perhaps use the name of the paper and who wrote it and use that as the link instead. It is really interesting and I rather enjoyed reading it, however, if possible I would add some more photos just to break up the text. Your glossary is good and well set out and the information displayed is quite easy to understand, however I would consider adding to this section as there were some other words throughout the page which were in need of a slight description. You have an excellent use of references which is great, but I would have another look at reference 11 as there is no text, only an arrow.

'''Abnormal vision'''

Your introduction is rather succinct which I like but I would encourage you to put references in this section. I would also suggest that you split it into 2 paragraphs to make it easier to read. Perhaps maybe you could put a photo of a normal eye in this section to show what it should look like, and then throughout the paper as you discuss the abnormal developments, you it could give the reader a better understanding as to how exactly this has altered the eye using the comparison.

The Normal eye development section is good as it provides a way for the reader to compare the differences in progression when referring to the different abnormalities listed below. However I would possibly suggest this to be put in a table, with perhaps a sentence at the top saying something along the lines of in order to fully comprehend abnormal development, an understanding of normal eye development is important - that way the reader can understand why you put this section in. I would also suggest a picture here.

The abnormal lens development section is clearly very well researched with a wide range of references. I like how you have separated the development in to the different sections of the eye as this can give a more thorough insight into these abnormalities. I think this section has been well written, and the only suggestion I would have would be in regards to the photo presented. Perhaps include some arrows to point at the sections you’re talking about and discuss what the nuclear area of the lens is?

The anormal corneal development and the abnormal retinal development are very descriptive and well referenced. I would perhaps look at moving the photo in the corneal development up a bit more and again I would provide more of a description of what is shown. If possible, I would try and make the abnormal retinal photo bigger.

Ocular manifestations is a bit confusing as im not sure if it’s a new heaing all together of if it is supposed to be part of the broad category of abnormalities. Your genetic section is well researched, I would just be careful in referencing the same paper too many times (25 is listed 5 times in this section) and perhaps try and find some other papers which compliment this research? I would probably put your reseach timeline at the bottome and include all of the treatment and clinical manifestation flowing on from each other. Note that in the research timeline, this is purely from one source, reference 26, and I would advise that you find alternative sources as well – im sure there would be individual research papers for each new date??

The anophthalmia section im assuming is still part of genetic abnormalities and I would recommend starting with the genes which are affected – to create a flow on effect. Other than that it is well references and easy to read. In regards to your photo I would have a description of what the photo is about in the enlarged view to assist with the readers comprehension. Also, at what point can these abnormalities be detected in the womb – either from an ultrasound or from sampling of the genes or something - and does this have an affect on whether the mother keeps the child or not? I think the environmental causes of abnormalities are good and I would suggest that you add photos here to break up the text and also to give us an understanding of what happens.

Finally, your glossary needs a fair few more words in there as to help with our understanding. You have many references which is great, however take a loot at 46 – 49 – they all seem to be the same? It would be appropriate to merge them into one reference.

===Lab 9 ===

'''1. 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.'''

<pubmed>21490060</pubmed>

This research paper wanted to determine if Cdk4 has a role in embryonic pancreas development. The study required embryos being harvested from mice (Cdk4+/+, Cdk4–/– and Cdk4R24C) 1 hour after the discovery of the vaginal plug. The results indicated that Cdk4 is needed for growth and morphogenesis of the developing pancreas. Cdk4 deficiency decreases the size of the pancreas due to diminished mesenchyme development and less Pdx1+ cells. The results allude to the fact that Cdk4 promotes the Beta cell growth from the signalling transcription factor E2f1 to assist in the proliferation of Ngn3+endocrine precursors. Cdk4 thus is seen as an imperative regulator of the early developmental stages of the pancreas which regulates the growth of the endocrine precursors and pancreatic progenitors.

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

The teeth development necessitates the epithelial/ mesenchymal interaction between the ectoderm of the first pharyngeal arch along with ectomesenchymal cells of the neural crest . The tooth bud is the name given to the collection of cells which will later form a tooth <ref><pubmed>12615136</pubmed></ref>. There are 3 sections which contribute to the [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00019-9&isbn=978-1-4377-2002-0&uniqId=369704599-2#4-u1.0-B978-1-4377-2002-0..00019-9--s0055| developing teeth]:
# The enamel organ: The cells of the inner enamel epithelium of the enamel organ form the ameloblasts which differentiates and produces the enamel.
# The dental papilla: This is formed by the neural crest and cells from an unknown origin <ref><pubmed>21425080</pubmed></ref>. These cells develop into odontoblasts (or dentin forming cells). The mesenchymal cells contribute to the formation of the tooth pulp.
# The dental follicle: This produces 3 different cells. Cementoblasts create the cementum of the tooth. The osteoblasts create the alveolar bone around the tooth roots. Finally, the fibroblasts form the periodontal ligaments which attach the teeth to the alveolar bone.

Therefore, the ectoderm, neural crest and mesoderm all contribute to the development of the tooth.

===Lab 11 ===

<pubmed>22495829</pubmed>

In this research article, long term expandable neuro-epithelial like stem cells (It-NES) produced from the adult human fibroblast derived iPSCs were transplanted into the areas of stroke in mice and rat brains. Human induced pluripotent stem cells were produced and then were transformed into neuroepithelial like stem cells. The mice and rats incurred a middle cerebral artery occlusion and a week later, the human induced pluripotent stem cells were transplanted intracranially highlighted with a green fluorescent protein. 9 weeks following the transplant of the stem cells, the mice and rats were injected with 2% fluro-gold. Subsequently behaviourable tests along with cell counting and VEGF immunoreactivity took place to determine the effect of the induced pluripotent stem cells.

The results indicated that the transplanted neuro-epithelial like stem cells lead to an improved recovery of the motor deficit. The noted neuronal markers in the graft area at 10 week post transplantation, however they believe that recovery occurred much earlier on due to the progress they saw. This could be due to additional mechanisms working with the neuronal replacement. Notably, behavioural recovery was increased in both the mice and rats regardless if they had been transplanted with the neuroepithelial like stem cells.

The researchers believe that the raised levels of VEGF in the animals with the transplants were found to be important for minimising the inflammation and the neovascularisation in the peri infarct region. The transplanted cells also showed characteristic neuronal morphologies and had markers which showed that they had differentiated into different neuron subtypes. Additionally, through the electrophysical data, the induced pluripotent stem cells indicated they were able to differentiate into functional neurons creating normal connections with the host brain, along with synaptic input from the neurons of the host brain. After approximately 5 months, the transplanted cells showed electrophysiological qualities of normal mature neurons. This article was the first of its kind to show that induced pluripotent stem cells are able to replace sections of a stroke damaged brain.

===References===
<references/>

User:Z3292017

2012-10-16T21:29:11Z

Z3292017: /* Lab 9 */

=='''Lab Attendance'''==

Lab 1 - [[User:Z3292017|Z3292017]] 10:15, 25 July 2012 (EST)

Lab 2 - [[User:Z3292017|Z3292017]] 10:17, 1 July 2012 (EST)

Lab 3 - [[User:Z3292017|Z3292017]] 10:13, 8 August 2012 (EST)

Lab 4 - [[User:Z3292017|Z3292017]] 11:23, 15 August 2012 (EST)

Lab 5 - [[User:Z3292017|Z3292017]] 10:34, 22 August 2012 (EST)

Lab 6 - [[User:Z3292017|Z3292017]] 11:31, 29 August 2012 (EST)

Lab 7 - [[User:Z3292017|Z3292017]] 10:14, 12 September 2012 (EST)

Lab 8 - [[User:Z3292017|Z3292017]] 10:13, 19 September 2012 (EST)

Lab 9 - [[User:Z3292017|Z3292017]] 11:11, 26 September 2012 (EST)

Lab 10 - [[User:Z3292017|Z3292017]] 11:06, 3 October 2012 (EST)

Lab 11 - [[User:Z3292017|Z3292017]] 10:05, 10 October 2012 (EST)

==Lab 1 - [[User:Z3292017|Z3292017]]==

'''Lab 1 Online Assessment'''

''Question 1: Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique:''

The origin of IVF can be dated from the late 19th Century where embryo transplantation in rabbits was discovered by Walter Heape. The development of IVF was due to a cascade of events during the 20th century. Pincus and Enzmann from Harvard University suggested the possibility that mammalian eggs are able to develop normally in vitro in 1934. In 1948 Menken and Rock exposed 138 oocytes to spermatozoa in vitro. In 1959, Change was able to provide evidence for IVF by fertilising rabbit eggs with capicated sperm and thus achieve birth. From 1965 Robert Edwards attempted to fertilise human oocytes in vitro. In 1968 Edwards successfully fertilised a human egg using a human culture media he developed. Finally after years of research and failed attempts, the first test tube baby was born in 1978.
Robert Edwards was awarded the Nobel Prize in Physiology and Medicine in 2010 due to his immense development and contribution of IVF.

'''References'''
<references/>
#http://www.ivf-worldwide.com/ivf-history.html
#http://en.wikipedia.org/wiki/In_vitro_fertilisation
#http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/

''Question 2: Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings:''

Cleavage speed and implantation potential of early cleavage embryos in IVF or ICSI cycles by Lee, Lin and Hwu (July, 2012) attempted to determine the correlation of early embryo cleavage, its speed and the potential implantation rates for IVF. Their definition of early cleavage was embryonic mitosis occurring 25-27 hours after insemination. The embryos’ (day 3) cleavage speed was assessed and rated into 3 groups: rapid (more than 9 cells), normal (7-8 cells) and slow (less than 7 cells) along with their morphological quality being either good or poor. Normal fertilisation was determined by the presence of 2 nuclei and 2 polar bodies. 25-27 hours after IVF an early cleavage examination took place to determine which embryos had already cleaved. They embryos were then examined for their quality from 66-68 hours after IVF.

Early cleavage emrbyos developed normally in comparison to non early cleavage embryos. Notably, the early cleavage embryos produced a greater amount of “good quality” embryos and subsequently the implantation rate was sufficiently greater with early cleavage embryos. This finding is of great importance as embryo morphology is the most important tool to select the best embryo to transfer andthus increase the rates of implantation, pregnancy and live birth.

'''References'''

Lee MJ, Lee RK, Lin MH, Hwu YM '''Cleavage speed and implantation potential of early-cleavage embryos in IVF or ICSI cycles.''' J Assist Reprod Genet. 2012 Jul 25 PMID: 22825967

==Lab 2 - [[User:Z3292017|Z3292017]]==

'''Lab 2 Online Assessment'''

''Question 1: Image from journal source''

[[File:zygote.jpg]]

Zygotes showing different distribution of NPB in the 2PN and different PB alignment <ref>Alessia Nicoli, Francesco Capodanno, Lucia Moscato, Ilaria Rondini, Maria T Villani, Antonella Tuzio, and Giovanni B La Sala (2010) '''Analysis of pronuclear zygote configurations in 459 clinical pregnancies obtained with assisted reproductive technique procedures''' Department of Obstetrics and Gynecology, Arcispedale Santa Maria Nuova, Reprod Biol Endocrinol. 2010; 8: 77. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902489/?tool=pubmed NCBI]</ref>

===Reference===

<references/>

''Question 2: Identify a protein associated with the implantation process, including a brief description of the protein's role''

Proprotein convertase 6 (PC6) is a necessary regulatory molecule for embryo implantation which generates bioactive proteins such as growth factors, peptide hormones and adhesion molecules. It is produced in the uterine stromal cells in particular at the embryo attachment site throughout early pregnancy in mice. In order for implantation to occur, the uterus ungergoes morphological and physiological changes, one being differentiation of endometrial stromal cells.

Studies have shown that PC6 mRNA is upregulated in particularly at the site of embryo attachment in the mouse uterus, being predominantly at the antimesometrial pole undergoing decidualisation. These results imply that PC6 is associated with decidualisation. From this study, the researchers were able to determine that endometrial PC6 is imperative for maternal stromal decidual response for an implanting embryo during the time of implantation. They discovered that endometrial PC6 is produced explicitly in decidual cells (the vascular and cellular changes in a uterus in preparation for pregnancy) and is not found in other cells as well as the embryo. Similarly, they noted that inhibition of the production of PC6 early on (around day 3.5) using anti-PC6 MO blocked the decidualisation and thus impeded implantation. Notably, PC6 is produced in the late secretory phase of the menstrual cycle in preparation for implantation.

===Reference===

Guiying Nie, Ying Li, Min Wang, Yi Xun Liu, Jock K. Findlay and Lois A. Salamonsen '''Inhibiting Uterine PC6 Blocks Embryo Implantation: An Obligatory Role for a Proprotein Convertase in Fertility''' Biology of Reproduction April 1, 2005 vol. 72 no. 4 1029-1036. [http://www.biolreprod.org/content/72/4/1029.long Biology of Reproduction]

==Lab 3 - [[User:Z3292017|Z3292017]]==

'''Lab 3 Online Assessment'''

''Question 1: Difference between post fertilisation age and gestational age''

Post fertilisation age (embryonic age) is dated at fertilisation of the egg which is approximately 2 weeks after the gestational age. This however is far less easy to determine than the gestational age as they calculate the time of ovulation as the oocyte is normally fertilised within the 12 hour period after ovulation.

Gestational age is the date of the beginning of the last normal menstrual period and is clinically more commonly used as it is a much easier method to calculate. Notably, the crown-rump length of the fetus along with the head and femur length are later used to confirm the estimated age of the fetus.

[http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00005-9--s0050&isbn=978-1-4377-2002-0&uniqId=351438666-2#4-u1.0-B978-1-4377-2002-0..00005-9--s0075| Estimation of gestational and embryonic age]

''Question 2: 3 different types of tissues formed from somites''

Ventromedially, the somite differentiates into the sclerotome which forms the vertebrae and the ribs. Studies have shown that Pax-1 is essential for the ventral sclerotome differentiation. The sclerotome differentiates into the vertebrae and ribs through bone formation. [http://www.ncbi.nlm.nih.gov/pubmed/8026324 Role of Pax-1 in skeleton development]. This is primarily initiated with mesenchymal cells which assists the formation of the pre-cartilage mass via chrondrocytes and subsequently cartilage formation. Bone then develops through the replacement of cartilaginous tissue with bone tissue. [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00014-X&isbn=978-1-4377-2002-0&uniqId=351438666-4 Development of bone and cartilage]

Dorsolaterally, the somite first differentiates into the dermomyotome which then creates 2 regions. The myotome region forms primordial muscle cells (myoblasts) and the dermatome region forms the fibroblasts (dermis). [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00015-1&isbn=978-1-4377-2002-0&uniqId=351438666-4#4-u1.0-B978-1-4377-2002-0..00015-1 Development of Muscle]

Dermatome along with Neurotrophin-3 assists with the early formation of the dermis. [http://www.ncbi.nlm.nih.gov/pubmed/7671821 Role of Neurotrophin-3] The dermal papillae consist mainly of fibroblasts and is located close to the epidermis. It contains both elastin and collagen fibres (produced by fibroblasts) with the elastin fibres perpendicular to the surface of the skin. The reticular dermis accounts for the majority of the dermis with multidirectional elastin and collagen fibres. Notably, in the dermal papillae, a plexus consisting of numerous blood vessels are found but do not penetrate into the epidermis. Some nerves within this region do penetrate through to the epidermis via free nerve endings which are linked to nerve corpuscles, such as Meissner's plexus. [http://www.skin-science.com/_int/_en/topic/topic_sousrub.aspx?tc=SKIN_SCIENCE_ROOT%5EAN_ORGAN_REVEALED%5ETHE_DERMIS&cur=THE_DERMIS Dermis formation]

Myotomes are separated into [http://embryology.med.unsw.edu.au/embryology/index.php?title=Musculoskeletal_System_-_Muscle_Development#Myotome epaxial muscles and hypaxial muscles] via primordial muscle cells . The epaxial muscles form the skeletal muscles dorsal to the vertebral column known as the erector spinae muscles. The hypaxial muscles form the ventral skeletal muscles which contribute to the lung and limb formation. The skeletal muscle fiber is long, cylindrical and multinucleated, with peripherally located nuclei.

==Lab 4 - [[User:Z3292017|Z3292017]]==

'''Lab 4 Online Assessment'''

''Question 1: 2 invasive prenatal diagnostic techniques related to the placenta:''

1. Amniocentesis:

A relatively common yet invasive procedure normally conducted between weeks 15-18 of gestation. A 22 gauge needle is inserted through the anterior abdominal and uterine walls (around the region of the umbilicus) of the mother into the amniotic cavity. Of the approximate 200mL volume that the mother is carrying at this early stage of pregnancy, only 15-20mL can be withdrawn safely. There is usually little risk when performing this procedure as an ultrasonography can be used concurrently to outline the fetal and placental position.

Amniocentesis is a procedure used to determine many genetic disorders such as Down Syndrome and also neural tube defects such as spina bifida cystica. [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00006-0--s0100&isbn=978-1-4377-2002-0&uniqId=352651422-2#4-u1.0-B978-1-4377-2002-0..00006-0--s0110| Amniocentesis - The Developing Human]

2. Chorionic Villus Sampling:

Trophoblastic tissue biopsies between 5-20 mg can be obtained through inserting a needle through the abdominal and uterine walls of the mother into the uterine cavity. This can also be completed transcervically using a polyethylene catheter through the cervix to obtain a chorionic villus sample. There is a slightly greater risk of miscarriage after this procedure has been performed when compared to amniocentesis (of around 1%).

Chorionic villus sampling is a procedure used to detect chromosomal abnormalities and also X linked disorders. The benefit of CVS over amniocentesis is that it can be performed between the 10th-12th week of gestation and thus giving an earlier diagnosis. [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00006-0--s0100&isbn=978-1-4377-2002-0&uniqId=352651422-2#4-u1.0-B978-1-4377-2002-0..00006-0--s0125| Chorionic Villus Sampling - The Developing Human]

''Question 2: Paper using cord stem cell therapeutically discussion of findings:''

Lim JY, Jeong CH, Jun JA, Kim SM, Ryu CH, Hou Y, Oh W, Chang JW, Jeun SS '''Therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of cerebral ischemia''' Stem Cell Res Ther. 2011; 2(5): 38 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3308035/?tool=pubmed| PMID: 21939558]

In this paper, the researchers investigated the effects of therapeutic potential of mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of stroke. Following this, the researchers then investigated whether the mesenchymal stem cells could enter and survive in the brain, and their potential to improve post stroke functional recovery. Mesenchymal stem cells (MSC) are a promising therapeutic strategy for the treatment of stroke due to their high proliferative capacity and also that they can be easily obtained.

The mesenchymal stem cells were injected intrathecally in some rats and intravenously in the others three days after Middle Coronary Artery Occlusion (MCAO) using isoflurane anesthesia. A 1cm incision was made over L3-L5 spinous processes and a neonatal lumbar puncture needed (25 gauge) was inserted into the spinal canal. MSCs (1 × 10^6) was diluted with 20 μl PBS being injected into the CSF over 30 seconds. Intravenously, MSCs (1 × 10^6) was diluted with 700 μl PBS were injected slowly for five minutes via an intravenous cannula situated in the tail vein. The presence and survival of the MSCs in the brain tissue was examined by immunohistochemistry. The rats were examined by their recovery of coordination of movement using both the Rotarod test and the adhesive removal test after the 1st, 2nd, 3rd and 4th week of stroke.

The results indicated that the MSC intrathecally receiving rats had an increased level of migrated cells to the ischemic area compared to the intravenous administration of MSCs. Additionally, many of the cells were expressing the mature neural lineage markers. Overall, the intrathecal administration of MSCs were more effective in reducing ischemic damage, yet proved to be similar to intravenous administration in promoting neurological recovery.

This study thus indicated a potential treatment for cerebral ischemia or neurodengerative disorders due to its ability to recover ischemic damaged tissue.

== Lab 7 ==

'''Lab 7 Online Assessment'''

''Question 1''

''(a) Definition of muscle satellite cell''

A muscle satellite cell is a quiescent mononucleated cell, which respond to injury by proliferating to form regenerated muscle and additional satellite cells, found between the basement membrane of specialised muscle fibres. [http://www.ncbi.nlm.nih.gov/pubmed/12757751| Muscle Satellite Cell PMID: 12757751]

''(b) Two examples of when satellite cells are activated''

Satellite cells are employed for skeletal muscle trauma and also disease.

* Muscle injury: When muscle injury occurs, the satellite cells are activated and will either form multinucleated myotubes to assist with muscle regeneration, or will form additional quiescent satellite cells in order to assist with more [http://www.ncbi.nlm.nih.gov/pubmed?term=The%20muscle%20satellite%20cell%20at%2050%3A%20the%20formative%20years| muscle regeneration]. Sambasivan et al. indicated in their 1993 study that other cells with regenerative potential depend on the satellite cell presence especially the Pax7 expressing satellite cells. [http://dev.biologists.org.wwwproxy0.library.unsw.edu.au/content/138/17/3647| Pax7-expressing satellite cells]

* Muscle disease: Research has shown that congenital myopathies such as Duchenne Muscular Dystrophy lead to a greater number of satellite cells than in normal muscle cells. Notably, the regenerative capacity of, for example Duchenne Muscular Dystrophy, is limited due to the severity and continuation of the disease. [http://genesdev.cshlp.org.wwwproxy0.library.unsw.edu.au/content/20/13/1692| Muscle stem cells in development, regeneration, and disease]

''Question 2: 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''

Spinal cord injury will result in partial or complete paralysis of the muscle innervation at or below the trauma level of the spinal cord resulting in atrophy. Some studies have noted that a some paralysed muscles due to spinal cord injury have an increase in force per cross sectional area of the muscle compared to normal in an attempt to maintains the muscle's normal strength. However, it is also important to note, the muscle cross sectional area significantly decreased. Due to the decrease in muscle, the study also indicated that there were increased levels of connective tissues and fat - thought to transfer more of the force to the tendon. Importantly, in chronic muscle denervation (greater than 50% of muscle size loss), the strength of the muscle (if there was any at all) has seriously deteriorated. [http://www.ibib.waw.pl/bbe/bbefulltext/bbe_25_3_039_ft.pdf| Muscle Atrophy after Human Spinal Cord Injury]

After a spinal cord injury the muscle fibre type pattern changes from a mix of type I and type II to predominantly type II fast glycolytic fibres. This is thought be an explanation of the quick muscle fatigue noted in rehabilitation. Notably, Burnham et al. discovered that the muscle fibre type change occurs in stages rather than an immediate effect and thus opens the door to more research to prevent the transformation of the muscle types from occurring, which is inidcated to be done within the first week or two following spinal cord injury. [http://www.ncbi.nlm.nih.gov/pubmed/9044514| Skeletal muscle fibre type transformation following spinal cord injury]

==Lab 8==

'''Lab 8 Online Assessment'''

'''Vision'''

The photo at the top of your page is a great choice and makes the site that much more appealing. The only suggestion I would have here is to potentially minimise the photo as it makes the contents section to the left of it hard to read. Your introduction is clear and concise and gives a good description of the eye. A slight adjustment I would make is perhaps to make it slightly longer giving a brief discussion about what is to be discussed on this page. Included in your introduction you have the anatomy of the eye. Firstly, would it be appropriate to include the histology as well, as it appears further down the page you discuss the cells, so perhaps if you gave a brief histological overview that could make the sections below easier for the reader to comprehend. I would probably add to that that if you were to include histology, to put the anatomy and histology into a new section just so it doesn’t clutter the introduction.

Your history, although I’m aware it ins’t finished, would read better if it were in a table and would also bring some more colour to the page. I’m assuming this will come when you finish this section, but it would be wise to include updated examples as well in order to show an adequate progression of the history.

The development section appears to be very thorough which is fantastic. It is rather clear that you have put a lot of research and time into this section. The introduction you have there is well written and again concise which is great. Additionally I like your use of photos just below it to further your explanation and also to break up the text. In regards to your photos, I would suggest perhaps a better description of them and to make sure you include where you got the photo from. If there were an explanation of the photo in simplistic terms, then I think the photos would be really beneficial.

The optic nerve section is well written but it appears to lack references?? In the first 3 paragraphs there are only 2 references. I would probably suggest that this information is backed up by additional sources as well. Also, with your hand drawn pictures (which are good), I would suggest an explanation on them when you open the picture up in another window. Your paragraph describing the 2 pictures, I would probably recommend that it become sintegrated within the text i.e. when you are talking about that part of it then include it there. I just think it would make it flow better that way – like you have done with figure 3.

The retina is good and well set out with pictures. However I noticed that you have used the exact references as before (3, 4)?? It would be really advisable to include many more references than what is listed. The same applies to the images as I said above, but good integration!

The ciliary body appears to be well researched and referenced. From the iris down there appears to be a lack of new references and also looks rather bland - so here I would suggest including additional photos from journal articles you have used. Also, it seems rather brief, I’m wondering whether there is more information about the embryological processes that could be included?

The current research is a good start, but there isn’t much of an explanation of the photo that is included and brief discussion of the research should probably be included. Are there additional research projects to include as well?

Finally, your references ar good but short. The fisrt 2 need to be put in the appropriate format. I would definitely suggest including many more references in order to make your information listed more valid.

'''Somatosensory development'''

I really like your introduction, I think that is is really informative and gives the reader a much clearer understanding of what this topic is about. Your references here need to be included in the reference section below but it appears that you have a good amount of references for the points depicted. At the end of the first paragraph it discusses a picture of the general organisation however there is not one there?? Also the inclusion of a picture would be agreat idea not only to further our understanding but also to break up the text and make it more appealing.

In your history of discoveries section I would probably recommend putting this in a colourful table, again to rbeak up the text, and also to make it easier to read. I would probably suggest here that you include a greater progression of discoveries to show the change of thinking over time. Note to also inlduce the appropriate referencing as shown in previous lab classes.

The central somatosensory differentiation is very expansive and informative. I would assume that you have put a lot of research into this section. Note that you have used pretty well the same references over and over. I would suggest that you include additional references to back up those statements as well. If those couple of references were the only ones saying that information, then I would suggest further researching to ensure that other journal articles don’t contradict this. The image is good and appears to show a good somatosensory pathway, however I would make the font bigger, so that it would not be imperative to enlarge the photo to read what is there. The picture has a discription when it is enlarged which is good, but I think it would also be appropriate to put the correct student information for the referencing.

In the Touch part, I noted that almost none of the text is refenced, which essentially makes the information listen invalid, so I would look into finding appropriate references here. Also, this section seems a bit dull with no pictures. Perhaps histological photos could be included here? I know we studied them in histology and this would make the section more interesting and also compliment the information stated. I would also suggest that those subheadings you don’t want in bold, you list in italic with two ‘ ‘ in order to separate it from the text below..

The Pain section probably needs to be set out better by using dot points? It appears that you have provided some excellent information but it is also important to put the references included with the reference section below. A photo here might be nice, perhaps of the different fibres if this can be found?

The Hot/Cold section is better set out and I like the appropriate referencing here. However, it appears that you are re-using the same references, so I would suggest some more research be done here to compliment your other references. It is better set out, however I would suggest some photos to be included if at all appropriate and can be found.

Pressure is similar to the pain section in the sense that the references really need to be put in the referencing section. It would also be advisable that you split the first paragraph up as it is rather long and not very appealing for one to read.

Current research section is good and concise. I like the use of the picture there, and I like the description that you have when you enlarge the picture. Is there any other current research happening now?

Finally, I would suggest adding more information outlining the development of these areas as I believe this to have been limited across the majority of sections. Although you are providing good reaseach and information describing these sections, as this is am embryology course, I would see it as appropriate that some sort of developmental progression is included – or if this is not known as of yet, for that to be stated. I would also highly recommend that you include a detailed glossary of words, as this is rather incomplete.

'''Taste development'''

The introduction section is very informative and I like the picture included discussing the 5 basic tastes which is interesting to read. I really enjoy your descriptions of bitter and sweet and find it interesting to read. I like the research you included in this section but I believe this needs to be referenced. Currently in the introduction you have only 1 references, so I would suggest that you find more to further validate your information (note that there are no references in the first paragraph). I like in your picture that you included a description. The cell biology section I would probably put in its own section with = = to break up the contend displayed. In this section it is clear that this has been researched however there have been no references listed at all here.

The taste map section has clearly been well researched yet poorly referenced. It would be interesting to look at if possible a progression of the understanding of the taste map. In the picture of the tongue, I would suggest that it has a better description on the enlarged image. However, some of this text is rather hard to read, such as the descriptions of the first and second order neurons. As you have included terms in there which would be foreign to most people, I would try to include either a picture to show exactly where these parts are such as the NTS which can give the reader a better understanding of what you’re saying. Note that you say things like “copious scientific conjecture surrounds…” however there is no references here! This section is well researched which is great, but I would really consider putting it into slightly easier terms to better comprehension.

In the cortical areas section, a similar approach applies: when describing locations of things such as the I/fO, you should really include a clear diagram as to where all of these are. I can see you included the section of the brain however don’t see it as too informative so a better description there would be appropriate. I would also note that you are repeating your references again, and it would be advisable that you find alternative information to include as well.

The timeline section is very informative and really stands out. I’m assuming you will be including the photos later this week. This is well written and gives a truly informative description of the embryological changes that occur. It will look much better and be better to understand once the photos have been included. Note that you have used the same references pretty well the whole time in this section. Although that paper may have a lot of information about what you are needing to talk about, I would also encourage you to research more papers in order to compliment the information you have listed.

The history of discoveries section is well set out and clear and concise. In some areas I would suggest a brief descripton of what you have written such as “PKD2L”, and also make sure you include the appropriate references as all I can see currently it numbers.

In the adult tongue and taste bud section, is this also what the tongue looks like from week 15? If not what changes occurs for it to form into what you have described as the adult tongue and what enhances these changes? This section is informative however it is really lacking references. The taste bud picture you have is quite good, but is that also what the taste bud looks like at 15 weeks?

The abnormalities section is really interesting and is rather enjoyable to read. Are they the only abnormalities that can happen to the tongue? How about environmental? Does alcohol, smoking or drugs affects its development of either the tongue or the taste buds? Additonally, your current research is very thorough and interesting. In regards to the photos you have there, I would make sure that they are set out appropriately, with the information that this is a student project.

Finally, the glossary needs to be highlighted to make it stand out and more words need to be included. Note that in your references, reference 5 can not be accessible, so make sure you fix that up. Overall, it was interesting to read and I enjoyed the display of photos that were also included!

'''Olfaction'''

Your introduction is good and concise giving a simple understanding of the olfactory system. Here I would suggest that you include what you’re about to discuss on the page. I also think you should include some references and maybe a photo in this section. The references to show that this information has been researched and the photo to break up the text and give the reader a simple understanding of the olfactory system.

The history of discovery section is clearly well researched and is well set out. However, I would suggest that you include brief descriptions of what has been described such as the Vomeronasal organ or the Nobel Prize which will further enhance the readers understanding. You have a good use of references there as well. In the picture that was included in this section, I would provide a more indepth description of what is drawn i.e. what the ectoderm is etc.

The timeline of developmental process is really well set out and easy to read. I would just make sure that every new point you include, you put it with a references as some of your points are not referenced at all and you need to be careful of that! I would also suggest that you put it in appropriate bullet points using the star key on your keyboard, that way it can be set out a bit better. Also, at the end of week 8, does this mean the olfactory system is complete by then? If so, then I would suggest you state that in that final week, if not, then what other small changes occur throughout the duration of the pregnancy? Also note that week 6 – 8 the references are either limited or not there, so I would recommend putting them in.

The anatomy of the olfactory system and the normal function are limited in information but also have only one reference between them. The images attached should really have more of a description when the picture is enlarged to give the reader a better understanding of what you’re talking about. Such as: diagram of olfactory bulb- what does it do and where is it located?

The abnormality section is rather indepth for 2 conditions, are there any other factors that come into play in regards to olfactory defects? Such as environmental? The Kallmann’s syndrome is really indepth and describes the clinical features, diagnosis and treatment, could this also be implementd with the Choanal atresia? Or are the same techniques used there? Also, be careful when you use shortening of words such as OB, you provided the HH in brackets first, so I would suggest the same is done with the olfactory bulb just to prevent confusion. I like your use of both images and give s a simple but good explanation of what you have been discussing (and also breaks up the text!). I like how you have provided a good description in the enlarged picture and it makes it easier for the reader to understand.

The current research section really shows that you have put a lot of effort in for this section. However, at the beginning of each new research you state either a study or a paper with a link, perhaps use the name of the paper and who wrote it and use that as the link instead. It is really interesting and I rather enjoyed reading it, however, if possible I would add some more photos just to break up the text. Your glossary is good and well set out and the information displayed is quite easy to understand, however I would consider adding to this section as there were some other words throughout the page which were in need of a slight description. You have an excellent use of references which is great, but I would have another look at reference 11 as there is no text, only an arrow.

'''Abnormal vision'''

Your introduction is rather succinct which I like but I would encourage you to put references in this section. I would also suggest that you split it into 2 paragraphs to make it easier to read. Perhaps maybe you could put a photo of a normal eye in this section to show what it should look like, and then throughout the paper as you discuss the abnormal developments, you it could give the reader a better understanding as to how exactly this has altered the eye using the comparison.

The Normal eye development section is good as it provides a way for the reader to compare the differences in progression when referring to the different abnormalities listed below. However I would possibly suggest this to be put in a table, with perhaps a sentence at the top saying something along the lines of in order to fully comprehend abnormal development, an understanding of normal eye development is important - that way the reader can understand why you put this section in. I would also suggest a picture here.

The abnormal lens development section is clearly very well researched with a wide range of references. I like how you have separated the development in to the different sections of the eye as this can give a more thorough insight into these abnormalities. I think this section has been well written, and the only suggestion I would have would be in regards to the photo presented. Perhaps include some arrows to point at the sections you’re talking about and discuss what the nuclear area of the lens is?

The anormal corneal development and the abnormal retinal development are very descriptive and well referenced. I would perhaps look at moving the photo in the corneal development up a bit more and again I would provide more of a description of what is shown. If possible, I would try and make the abnormal retinal photo bigger.

Ocular manifestations is a bit confusing as im not sure if it’s a new heaing all together of if it is supposed to be part of the broad category of abnormalities. Your genetic section is well researched, I would just be careful in referencing the same paper too many times (25 is listed 5 times in this section) and perhaps try and find some other papers which compliment this research? I would probably put your reseach timeline at the bottome and include all of the treatment and clinical manifestation flowing on from each other. Note that in the research timeline, this is purely from one source, reference 26, and I would advise that you find alternative sources as well – im sure there would be individual research papers for each new date??

The anophthalmia section im assuming is still part of genetic abnormalities and I would recommend starting with the genes which are affected – to create a flow on effect. Other than that it is well references and easy to read. In regards to your photo I would have a description of what the photo is about in the enlarged view to assist with the readers comprehension. Also, at what point can these abnormalities be detected in the womb – either from an ultrasound or from sampling of the genes or something - and does this have an affect on whether the mother keeps the child or not? I think the environmental causes of abnormalities are good and I would suggest that you add photos here to break up the text and also to give us an understanding of what happens.

Finally, your glossary needs a fair few more words in there as to help with our understanding. You have many references which is great, however take a loot at 46 – 49 – they all seem to be the same? It would be appropriate to merge them into one reference.

===Lab 9 ===

'''1. 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.'''

<pubmed>21490060</pubmed>

This research paper wanted to determine if Cdk4 has a role in embryonic pancreas development. The study required embryos being harvested from mice (Cdk4+/+, Cdk4–/– and Cdk4R24C) 1 hour after the discovery of the vaginal plug. The results indicated that Cdk4 is needed for growth and morphogenesis of the developing pancreas. Cdk4 deficiency decreases the size of the pancreas due to diminished mesenchyme development and less Pdx1+ cells. The results allude to the fact that Cdk4 promotes the Beta cell growth from the signalling transcription factor E2f1 to assist in the proliferation of Ngn3+endocrine precursors. Cdk4 thus is seen as an imperative regulator of the early developmental stages of the pancreas which regulates the growth of the endocrine precursors and pancreatic progenitors.

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

The teeth development necessitates the epithelial/ mesenchymal interaction between the ectoderm of the first pharyngeal arch along with ectomesenchymal cells of the neural crest . The tooth bud is the name given to the collection of cells which will later form a tooth <ref><pubmed>12615136</pubmed></ref>. There are 3 sections which contribute to the [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00019-9&isbn=978-1-4377-2002-0&uniqId=369704599-2#4-u1.0-B978-1-4377-2002-0..00019-9--s0055| developing teeth]:
# The enamel organ: The cells of the inner enamel epithelium of the enamel organ form the ameloblasts which differentiates and produces the enamel.
# The dental papilla: This is formed by the neural crest and cells from an unknown origin <ref><pubmed>21425080</pubmed></ref>. These cells develop into odontoblasts (or dentin forming cells). The mesenchymal cells contribute to the formation of the tooth pulp.
# The dental follicle: This produces 3 different cells. Cementoblasts create the cementum of the tooth. The osteoblasts create the alveolar bone around the tooth roots. Finally, the fibroblasts form the periodontal ligaments which attach the teeth to the alveolar bone.

Therefore, the ectoderm, neural crest and mesoderm all contribute to the development of the tooth.

===Lab 11 ===

<pubmed>22495829</pubmed>

===References===
<references/>

User:Z3292017

2012-10-09T23:05:56Z

Z3292017: /* Lab Attendance */

=='''Lab Attendance'''==

Lab 1 - [[User:Z3292017|Z3292017]] 10:15, 25 July 2012 (EST)

Lab 2 - [[User:Z3292017|Z3292017]] 10:17, 1 July 2012 (EST)

Lab 3 - [[User:Z3292017|Z3292017]] 10:13, 8 August 2012 (EST)

Lab 4 - [[User:Z3292017|Z3292017]] 11:23, 15 August 2012 (EST)

Lab 5 - [[User:Z3292017|Z3292017]] 10:34, 22 August 2012 (EST)

Lab 6 - [[User:Z3292017|Z3292017]] 11:31, 29 August 2012 (EST)

Lab 7 - [[User:Z3292017|Z3292017]] 10:14, 12 September 2012 (EST)

Lab 8 - [[User:Z3292017|Z3292017]] 10:13, 19 September 2012 (EST)

Lab 9 - [[User:Z3292017|Z3292017]] 11:11, 26 September 2012 (EST)

Lab 10 - [[User:Z3292017|Z3292017]] 11:06, 3 October 2012 (EST)

Lab 11 - [[User:Z3292017|Z3292017]] 10:05, 10 October 2012 (EST)

==Lab 1 - [[User:Z3292017|Z3292017]]==

'''Lab 1 Online Assessment'''

''Question 1: Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique:''

The origin of IVF can be dated from the late 19th Century where embryo transplantation in rabbits was discovered by Walter Heape. The development of IVF was due to a cascade of events during the 20th century. Pincus and Enzmann from Harvard University suggested the possibility that mammalian eggs are able to develop normally in vitro in 1934. In 1948 Menken and Rock exposed 138 oocytes to spermatozoa in vitro. In 1959, Change was able to provide evidence for IVF by fertilising rabbit eggs with capicated sperm and thus achieve birth. From 1965 Robert Edwards attempted to fertilise human oocytes in vitro. In 1968 Edwards successfully fertilised a human egg using a human culture media he developed. Finally after years of research and failed attempts, the first test tube baby was born in 1978.
Robert Edwards was awarded the Nobel Prize in Physiology and Medicine in 2010 due to his immense development and contribution of IVF.

'''References'''
<references/>
#http://www.ivf-worldwide.com/ivf-history.html
#http://en.wikipedia.org/wiki/In_vitro_fertilisation
#http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/

''Question 2: Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings:''

Cleavage speed and implantation potential of early cleavage embryos in IVF or ICSI cycles by Lee, Lin and Hwu (July, 2012) attempted to determine the correlation of early embryo cleavage, its speed and the potential implantation rates for IVF. Their definition of early cleavage was embryonic mitosis occurring 25-27 hours after insemination. The embryos’ (day 3) cleavage speed was assessed and rated into 3 groups: rapid (more than 9 cells), normal (7-8 cells) and slow (less than 7 cells) along with their morphological quality being either good or poor. Normal fertilisation was determined by the presence of 2 nuclei and 2 polar bodies. 25-27 hours after IVF an early cleavage examination took place to determine which embryos had already cleaved. They embryos were then examined for their quality from 66-68 hours after IVF.

Early cleavage emrbyos developed normally in comparison to non early cleavage embryos. Notably, the early cleavage embryos produced a greater amount of “good quality” embryos and subsequently the implantation rate was sufficiently greater with early cleavage embryos. This finding is of great importance as embryo morphology is the most important tool to select the best embryo to transfer andthus increase the rates of implantation, pregnancy and live birth.

'''References'''

Lee MJ, Lee RK, Lin MH, Hwu YM '''Cleavage speed and implantation potential of early-cleavage embryos in IVF or ICSI cycles.''' J Assist Reprod Genet. 2012 Jul 25 PMID: 22825967

==Lab 2 - [[User:Z3292017|Z3292017]]==

'''Lab 2 Online Assessment'''

''Question 1: Image from journal source''

[[File:zygote.jpg]]

Zygotes showing different distribution of NPB in the 2PN and different PB alignment <ref>Alessia Nicoli, Francesco Capodanno, Lucia Moscato, Ilaria Rondini, Maria T Villani, Antonella Tuzio, and Giovanni B La Sala (2010) '''Analysis of pronuclear zygote configurations in 459 clinical pregnancies obtained with assisted reproductive technique procedures''' Department of Obstetrics and Gynecology, Arcispedale Santa Maria Nuova, Reprod Biol Endocrinol. 2010; 8: 77. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902489/?tool=pubmed NCBI]</ref>

===Reference===

<references/>

''Question 2: Identify a protein associated with the implantation process, including a brief description of the protein's role''

Proprotein convertase 6 (PC6) is a necessary regulatory molecule for embryo implantation which generates bioactive proteins such as growth factors, peptide hormones and adhesion molecules. It is produced in the uterine stromal cells in particular at the embryo attachment site throughout early pregnancy in mice. In order for implantation to occur, the uterus ungergoes morphological and physiological changes, one being differentiation of endometrial stromal cells.

Studies have shown that PC6 mRNA is upregulated in particularly at the site of embryo attachment in the mouse uterus, being predominantly at the antimesometrial pole undergoing decidualisation. These results imply that PC6 is associated with decidualisation. From this study, the researchers were able to determine that endometrial PC6 is imperative for maternal stromal decidual response for an implanting embryo during the time of implantation. They discovered that endometrial PC6 is produced explicitly in decidual cells (the vascular and cellular changes in a uterus in preparation for pregnancy) and is not found in other cells as well as the embryo. Similarly, they noted that inhibition of the production of PC6 early on (around day 3.5) using anti-PC6 MO blocked the decidualisation and thus impeded implantation. Notably, PC6 is produced in the late secretory phase of the menstrual cycle in preparation for implantation.

===Reference===

Guiying Nie, Ying Li, Min Wang, Yi Xun Liu, Jock K. Findlay and Lois A. Salamonsen '''Inhibiting Uterine PC6 Blocks Embryo Implantation: An Obligatory Role for a Proprotein Convertase in Fertility''' Biology of Reproduction April 1, 2005 vol. 72 no. 4 1029-1036. [http://www.biolreprod.org/content/72/4/1029.long Biology of Reproduction]

==Lab 3 - [[User:Z3292017|Z3292017]]==

'''Lab 3 Online Assessment'''

''Question 1: Difference between post fertilisation age and gestational age''

Post fertilisation age (embryonic age) is dated at fertilisation of the egg which is approximately 2 weeks after the gestational age. This however is far less easy to determine than the gestational age as they calculate the time of ovulation as the oocyte is normally fertilised within the 12 hour period after ovulation.

Gestational age is the date of the beginning of the last normal menstrual period and is clinically more commonly used as it is a much easier method to calculate. Notably, the crown-rump length of the fetus along with the head and femur length are later used to confirm the estimated age of the fetus.

[http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00005-9--s0050&isbn=978-1-4377-2002-0&uniqId=351438666-2#4-u1.0-B978-1-4377-2002-0..00005-9--s0075| Estimation of gestational and embryonic age]

''Question 2: 3 different types of tissues formed from somites''

Ventromedially, the somite differentiates into the sclerotome which forms the vertebrae and the ribs. Studies have shown that Pax-1 is essential for the ventral sclerotome differentiation. The sclerotome differentiates into the vertebrae and ribs through bone formation. [http://www.ncbi.nlm.nih.gov/pubmed/8026324 Role of Pax-1 in skeleton development]. This is primarily initiated with mesenchymal cells which assists the formation of the pre-cartilage mass via chrondrocytes and subsequently cartilage formation. Bone then develops through the replacement of cartilaginous tissue with bone tissue. [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00014-X&isbn=978-1-4377-2002-0&uniqId=351438666-4 Development of bone and cartilage]

Dorsolaterally, the somite first differentiates into the dermomyotome which then creates 2 regions. The myotome region forms primordial muscle cells (myoblasts) and the dermatome region forms the fibroblasts (dermis). [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00015-1&isbn=978-1-4377-2002-0&uniqId=351438666-4#4-u1.0-B978-1-4377-2002-0..00015-1 Development of Muscle]

Dermatome along with Neurotrophin-3 assists with the early formation of the dermis. [http://www.ncbi.nlm.nih.gov/pubmed/7671821 Role of Neurotrophin-3] The dermal papillae consist mainly of fibroblasts and is located close to the epidermis. It contains both elastin and collagen fibres (produced by fibroblasts) with the elastin fibres perpendicular to the surface of the skin. The reticular dermis accounts for the majority of the dermis with multidirectional elastin and collagen fibres. Notably, in the dermal papillae, a plexus consisting of numerous blood vessels are found but do not penetrate into the epidermis. Some nerves within this region do penetrate through to the epidermis via free nerve endings which are linked to nerve corpuscles, such as Meissner's plexus. [http://www.skin-science.com/_int/_en/topic/topic_sousrub.aspx?tc=SKIN_SCIENCE_ROOT%5EAN_ORGAN_REVEALED%5ETHE_DERMIS&cur=THE_DERMIS Dermis formation]

Myotomes are separated into [http://embryology.med.unsw.edu.au/embryology/index.php?title=Musculoskeletal_System_-_Muscle_Development#Myotome epaxial muscles and hypaxial muscles] via primordial muscle cells . The epaxial muscles form the skeletal muscles dorsal to the vertebral column known as the erector spinae muscles. The hypaxial muscles form the ventral skeletal muscles which contribute to the lung and limb formation. The skeletal muscle fiber is long, cylindrical and multinucleated, with peripherally located nuclei.

==Lab 4 - [[User:Z3292017|Z3292017]]==

'''Lab 4 Online Assessment'''

''Question 1: 2 invasive prenatal diagnostic techniques related to the placenta:''

1. Amniocentesis:

A relatively common yet invasive procedure normally conducted between weeks 15-18 of gestation. A 22 gauge needle is inserted through the anterior abdominal and uterine walls (around the region of the umbilicus) of the mother into the amniotic cavity. Of the approximate 200mL volume that the mother is carrying at this early stage of pregnancy, only 15-20mL can be withdrawn safely. There is usually little risk when performing this procedure as an ultrasonography can be used concurrently to outline the fetal and placental position.

Amniocentesis is a procedure used to determine many genetic disorders such as Down Syndrome and also neural tube defects such as spina bifida cystica. [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00006-0--s0100&isbn=978-1-4377-2002-0&uniqId=352651422-2#4-u1.0-B978-1-4377-2002-0..00006-0--s0110| Amniocentesis - The Developing Human]

2. Chorionic Villus Sampling:

Trophoblastic tissue biopsies between 5-20 mg can be obtained through inserting a needle through the abdominal and uterine walls of the mother into the uterine cavity. This can also be completed transcervically using a polyethylene catheter through the cervix to obtain a chorionic villus sample. There is a slightly greater risk of miscarriage after this procedure has been performed when compared to amniocentesis (of around 1%).

Chorionic villus sampling is a procedure used to detect chromosomal abnormalities and also X linked disorders. The benefit of CVS over amniocentesis is that it can be performed between the 10th-12th week of gestation and thus giving an earlier diagnosis. [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00006-0--s0100&isbn=978-1-4377-2002-0&uniqId=352651422-2#4-u1.0-B978-1-4377-2002-0..00006-0--s0125| Chorionic Villus Sampling - The Developing Human]

''Question 2: Paper using cord stem cell therapeutically discussion of findings:''

Lim JY, Jeong CH, Jun JA, Kim SM, Ryu CH, Hou Y, Oh W, Chang JW, Jeun SS '''Therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of cerebral ischemia''' Stem Cell Res Ther. 2011; 2(5): 38 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3308035/?tool=pubmed| PMID: 21939558]

In this paper, the researchers investigated the effects of therapeutic potential of mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of stroke. Following this, the researchers then investigated whether the mesenchymal stem cells could enter and survive in the brain, and their potential to improve post stroke functional recovery. Mesenchymal stem cells (MSC) are a promising therapeutic strategy for the treatment of stroke due to their high proliferative capacity and also that they can be easily obtained.

The mesenchymal stem cells were injected intrathecally in some rats and intravenously in the others three days after Middle Coronary Artery Occlusion (MCAO) using isoflurane anesthesia. A 1cm incision was made over L3-L5 spinous processes and a neonatal lumbar puncture needed (25 gauge) was inserted into the spinal canal. MSCs (1 × 10^6) was diluted with 20 μl PBS being injected into the CSF over 30 seconds. Intravenously, MSCs (1 × 10^6) was diluted with 700 μl PBS were injected slowly for five minutes via an intravenous cannula situated in the tail vein. The presence and survival of the MSCs in the brain tissue was examined by immunohistochemistry. The rats were examined by their recovery of coordination of movement using both the Rotarod test and the adhesive removal test after the 1st, 2nd, 3rd and 4th week of stroke.

The results indicated that the MSC intrathecally receiving rats had an increased level of migrated cells to the ischemic area compared to the intravenous administration of MSCs. Additionally, many of the cells were expressing the mature neural lineage markers. Overall, the intrathecal administration of MSCs were more effective in reducing ischemic damage, yet proved to be similar to intravenous administration in promoting neurological recovery.

This study thus indicated a potential treatment for cerebral ischemia or neurodengerative disorders due to its ability to recover ischemic damaged tissue.

== Lab 7 ==

'''Lab 7 Online Assessment'''

''Question 1''

''(a) Definition of muscle satellite cell''

A muscle satellite cell is a quiescent mononucleated cell, which respond to injury by proliferating to form regenerated muscle and additional satellite cells, found between the basement membrane of specialised muscle fibres. [http://www.ncbi.nlm.nih.gov/pubmed/12757751| Muscle Satellite Cell PMID: 12757751]

''(b) Two examples of when satellite cells are activated''

Satellite cells are employed for skeletal muscle trauma and also disease.

* Muscle injury: When muscle injury occurs, the satellite cells are activated and will either form multinucleated myotubes to assist with muscle regeneration, or will form additional quiescent satellite cells in order to assist with more [http://www.ncbi.nlm.nih.gov/pubmed?term=The%20muscle%20satellite%20cell%20at%2050%3A%20the%20formative%20years| muscle regeneration]. Sambasivan et al. indicated in their 1993 study that other cells with regenerative potential depend on the satellite cell presence especially the Pax7 expressing satellite cells. [http://dev.biologists.org.wwwproxy0.library.unsw.edu.au/content/138/17/3647| Pax7-expressing satellite cells]

* Muscle disease: Research has shown that congenital myopathies such as Duchenne Muscular Dystrophy lead to a greater number of satellite cells than in normal muscle cells. Notably, the regenerative capacity of, for example Duchenne Muscular Dystrophy, is limited due to the severity and continuation of the disease. [http://genesdev.cshlp.org.wwwproxy0.library.unsw.edu.au/content/20/13/1692| Muscle stem cells in development, regeneration, and disease]

''Question 2: 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''

Spinal cord injury will result in partial or complete paralysis of the muscle innervation at or below the trauma level of the spinal cord resulting in atrophy. Some studies have noted that a some paralysed muscles due to spinal cord injury have an increase in force per cross sectional area of the muscle compared to normal in an attempt to maintains the muscle's normal strength. However, it is also important to note, the muscle cross sectional area significantly decreased. Due to the decrease in muscle, the study also indicated that there were increased levels of connective tissues and fat - thought to transfer more of the force to the tendon. Importantly, in chronic muscle denervation (greater than 50% of muscle size loss), the strength of the muscle (if there was any at all) has seriously deteriorated. [http://www.ibib.waw.pl/bbe/bbefulltext/bbe_25_3_039_ft.pdf| Muscle Atrophy after Human Spinal Cord Injury]

After a spinal cord injury the muscle fibre type pattern changes from a mix of type I and type II to predominantly type II fast glycolytic fibres. This is thought be an explanation of the quick muscle fatigue noted in rehabilitation. Notably, Burnham et al. discovered that the muscle fibre type change occurs in stages rather than an immediate effect and thus opens the door to more research to prevent the transformation of the muscle types from occurring, which is inidcated to be done within the first week or two following spinal cord injury. [http://www.ncbi.nlm.nih.gov/pubmed/9044514| Skeletal muscle fibre type transformation following spinal cord injury]

==Lab 8==

'''Lab 8 Online Assessment'''

'''Vision'''

The photo at the top of your page is a great choice and makes the site that much more appealing. The only suggestion I would have here is to potentially minimise the photo as it makes the contents section to the left of it hard to read. Your introduction is clear and concise and gives a good description of the eye. A slight adjustment I would make is perhaps to make it slightly longer giving a brief discussion about what is to be discussed on this page. Included in your introduction you have the anatomy of the eye. Firstly, would it be appropriate to include the histology as well, as it appears further down the page you discuss the cells, so perhaps if you gave a brief histological overview that could make the sections below easier for the reader to comprehend. I would probably add to that that if you were to include histology, to put the anatomy and histology into a new section just so it doesn’t clutter the introduction.

Your history, although I’m aware it ins’t finished, would read better if it were in a table and would also bring some more colour to the page. I’m assuming this will come when you finish this section, but it would be wise to include updated examples as well in order to show an adequate progression of the history.

The development section appears to be very thorough which is fantastic. It is rather clear that you have put a lot of research and time into this section. The introduction you have there is well written and again concise which is great. Additionally I like your use of photos just below it to further your explanation and also to break up the text. In regards to your photos, I would suggest perhaps a better description of them and to make sure you include where you got the photo from. If there were an explanation of the photo in simplistic terms, then I think the photos would be really beneficial.

The optic nerve section is well written but it appears to lack references?? In the first 3 paragraphs there are only 2 references. I would probably suggest that this information is backed up by additional sources as well. Also, with your hand drawn pictures (which are good), I would suggest an explanation on them when you open the picture up in another window. Your paragraph describing the 2 pictures, I would probably recommend that it become sintegrated within the text i.e. when you are talking about that part of it then include it there. I just think it would make it flow better that way – like you have done with figure 3.

The retina is good and well set out with pictures. However I noticed that you have used the exact references as before (3, 4)?? It would be really advisable to include many more references than what is listed. The same applies to the images as I said above, but good integration!

The ciliary body appears to be well researched and referenced. From the iris down there appears to be a lack of new references and also looks rather bland - so here I would suggest including additional photos from journal articles you have used. Also, it seems rather brief, I’m wondering whether there is more information about the embryological processes that could be included?

The current research is a good start, but there isn’t much of an explanation of the photo that is included and brief discussion of the research should probably be included. Are there additional research projects to include as well?

Finally, your references ar good but short. The fisrt 2 need to be put in the appropriate format. I would definitely suggest including many more references in order to make your information listed more valid.

'''Somatosensory development'''

I really like your introduction, I think that is is really informative and gives the reader a much clearer understanding of what this topic is about. Your references here need to be included in the reference section below but it appears that you have a good amount of references for the points depicted. At the end of the first paragraph it discusses a picture of the general organisation however there is not one there?? Also the inclusion of a picture would be agreat idea not only to further our understanding but also to break up the text and make it more appealing.

In your history of discoveries section I would probably recommend putting this in a colourful table, again to rbeak up the text, and also to make it easier to read. I would probably suggest here that you include a greater progression of discoveries to show the change of thinking over time. Note to also inlduce the appropriate referencing as shown in previous lab classes.

The central somatosensory differentiation is very expansive and informative. I would assume that you have put a lot of research into this section. Note that you have used pretty well the same references over and over. I would suggest that you include additional references to back up those statements as well. If those couple of references were the only ones saying that information, then I would suggest further researching to ensure that other journal articles don’t contradict this. The image is good and appears to show a good somatosensory pathway, however I would make the font bigger, so that it would not be imperative to enlarge the photo to read what is there. The picture has a discription when it is enlarged which is good, but I think it would also be appropriate to put the correct student information for the referencing.

In the Touch part, I noted that almost none of the text is refenced, which essentially makes the information listen invalid, so I would look into finding appropriate references here. Also, this section seems a bit dull with no pictures. Perhaps histological photos could be included here? I know we studied them in histology and this would make the section more interesting and also compliment the information stated. I would also suggest that those subheadings you don’t want in bold, you list in italic with two ‘ ‘ in order to separate it from the text below..

The Pain section probably needs to be set out better by using dot points? It appears that you have provided some excellent information but it is also important to put the references included with the reference section below. A photo here might be nice, perhaps of the different fibres if this can be found?

The Hot/Cold section is better set out and I like the appropriate referencing here. However, it appears that you are re-using the same references, so I would suggest some more research be done here to compliment your other references. It is better set out, however I would suggest some photos to be included if at all appropriate and can be found.

Pressure is similar to the pain section in the sense that the references really need to be put in the referencing section. It would also be advisable that you split the first paragraph up as it is rather long and not very appealing for one to read.

Current research section is good and concise. I like the use of the picture there, and I like the description that you have when you enlarge the picture. Is there any other current research happening now?

Finally, I would suggest adding more information outlining the development of these areas as I believe this to have been limited across the majority of sections. Although you are providing good reaseach and information describing these sections, as this is am embryology course, I would see it as appropriate that some sort of developmental progression is included – or if this is not known as of yet, for that to be stated. I would also highly recommend that you include a detailed glossary of words, as this is rather incomplete.

'''Taste development'''

The introduction section is very informative and I like the picture included discussing the 5 basic tastes which is interesting to read. I really enjoy your descriptions of bitter and sweet and find it interesting to read. I like the research you included in this section but I believe this needs to be referenced. Currently in the introduction you have only 1 references, so I would suggest that you find more to further validate your information (note that there are no references in the first paragraph). I like in your picture that you included a description. The cell biology section I would probably put in its own section with = = to break up the contend displayed. In this section it is clear that this has been researched however there have been no references listed at all here.

The taste map section has clearly been well researched yet poorly referenced. It would be interesting to look at if possible a progression of the understanding of the taste map. In the picture of the tongue, I would suggest that it has a better description on the enlarged image. However, some of this text is rather hard to read, such as the descriptions of the first and second order neurons. As you have included terms in there which would be foreign to most people, I would try to include either a picture to show exactly where these parts are such as the NTS which can give the reader a better understanding of what you’re saying. Note that you say things like “copious scientific conjecture surrounds…” however there is no references here! This section is well researched which is great, but I would really consider putting it into slightly easier terms to better comprehension.

In the cortical areas section, a similar approach applies: when describing locations of things such as the I/fO, you should really include a clear diagram as to where all of these are. I can see you included the section of the brain however don’t see it as too informative so a better description there would be appropriate. I would also note that you are repeating your references again, and it would be advisable that you find alternative information to include as well.

The timeline section is very informative and really stands out. I’m assuming you will be including the photos later this week. This is well written and gives a truly informative description of the embryological changes that occur. It will look much better and be better to understand once the photos have been included. Note that you have used the same references pretty well the whole time in this section. Although that paper may have a lot of information about what you are needing to talk about, I would also encourage you to research more papers in order to compliment the information you have listed.

The history of discoveries section is well set out and clear and concise. In some areas I would suggest a brief descripton of what you have written such as “PKD2L”, and also make sure you include the appropriate references as all I can see currently it numbers.

In the adult tongue and taste bud section, is this also what the tongue looks like from week 15? If not what changes occurs for it to form into what you have described as the adult tongue and what enhances these changes? This section is informative however it is really lacking references. The taste bud picture you have is quite good, but is that also what the taste bud looks like at 15 weeks?

The abnormalities section is really interesting and is rather enjoyable to read. Are they the only abnormalities that can happen to the tongue? How about environmental? Does alcohol, smoking or drugs affects its development of either the tongue or the taste buds? Additonally, your current research is very thorough and interesting. In regards to the photos you have there, I would make sure that they are set out appropriately, with the information that this is a student project.

Finally, the glossary needs to be highlighted to make it stand out and more words need to be included. Note that in your references, reference 5 can not be accessible, so make sure you fix that up. Overall, it was interesting to read and I enjoyed the display of photos that were also included!

'''Olfaction'''

Your introduction is good and concise giving a simple understanding of the olfactory system. Here I would suggest that you include what you’re about to discuss on the page. I also think you should include some references and maybe a photo in this section. The references to show that this information has been researched and the photo to break up the text and give the reader a simple understanding of the olfactory system.

The history of discovery section is clearly well researched and is well set out. However, I would suggest that you include brief descriptions of what has been described such as the Vomeronasal organ or the Nobel Prize which will further enhance the readers understanding. You have a good use of references there as well. In the picture that was included in this section, I would provide a more indepth description of what is drawn i.e. what the ectoderm is etc.

The timeline of developmental process is really well set out and easy to read. I would just make sure that every new point you include, you put it with a references as some of your points are not referenced at all and you need to be careful of that! I would also suggest that you put it in appropriate bullet points using the star key on your keyboard, that way it can be set out a bit better. Also, at the end of week 8, does this mean the olfactory system is complete by then? If so, then I would suggest you state that in that final week, if not, then what other small changes occur throughout the duration of the pregnancy? Also note that week 6 – 8 the references are either limited or not there, so I would recommend putting them in.

The anatomy of the olfactory system and the normal function are limited in information but also have only one reference between them. The images attached should really have more of a description when the picture is enlarged to give the reader a better understanding of what you’re talking about. Such as: diagram of olfactory bulb- what does it do and where is it located?

The abnormality section is rather indepth for 2 conditions, are there any other factors that come into play in regards to olfactory defects? Such as environmental? The Kallmann’s syndrome is really indepth and describes the clinical features, diagnosis and treatment, could this also be implementd with the Choanal atresia? Or are the same techniques used there? Also, be careful when you use shortening of words such as OB, you provided the HH in brackets first, so I would suggest the same is done with the olfactory bulb just to prevent confusion. I like your use of both images and give s a simple but good explanation of what you have been discussing (and also breaks up the text!). I like how you have provided a good description in the enlarged picture and it makes it easier for the reader to understand.

The current research section really shows that you have put a lot of effort in for this section. However, at the beginning of each new research you state either a study or a paper with a link, perhaps use the name of the paper and who wrote it and use that as the link instead. It is really interesting and I rather enjoyed reading it, however, if possible I would add some more photos just to break up the text. Your glossary is good and well set out and the information displayed is quite easy to understand, however I would consider adding to this section as there were some other words throughout the page which were in need of a slight description. You have an excellent use of references which is great, but I would have another look at reference 11 as there is no text, only an arrow.

'''Abnormal vision'''

Your introduction is rather succinct which I like but I would encourage you to put references in this section. I would also suggest that you split it into 2 paragraphs to make it easier to read. Perhaps maybe you could put a photo of a normal eye in this section to show what it should look like, and then throughout the paper as you discuss the abnormal developments, you it could give the reader a better understanding as to how exactly this has altered the eye using the comparison.

The Normal eye development section is good as it provides a way for the reader to compare the differences in progression when referring to the different abnormalities listed below. However I would possibly suggest this to be put in a table, with perhaps a sentence at the top saying something along the lines of in order to fully comprehend abnormal development, an understanding of normal eye development is important - that way the reader can understand why you put this section in. I would also suggest a picture here.

The abnormal lens development section is clearly very well researched with a wide range of references. I like how you have separated the development in to the different sections of the eye as this can give a more thorough insight into these abnormalities. I think this section has been well written, and the only suggestion I would have would be in regards to the photo presented. Perhaps include some arrows to point at the sections you’re talking about and discuss what the nuclear area of the lens is?

The anormal corneal development and the abnormal retinal development are very descriptive and well referenced. I would perhaps look at moving the photo in the corneal development up a bit more and again I would provide more of a description of what is shown. If possible, I would try and make the abnormal retinal photo bigger.

Ocular manifestations is a bit confusing as im not sure if it’s a new heaing all together of if it is supposed to be part of the broad category of abnormalities. Your genetic section is well researched, I would just be careful in referencing the same paper too many times (25 is listed 5 times in this section) and perhaps try and find some other papers which compliment this research? I would probably put your reseach timeline at the bottome and include all of the treatment and clinical manifestation flowing on from each other. Note that in the research timeline, this is purely from one source, reference 26, and I would advise that you find alternative sources as well – im sure there would be individual research papers for each new date??

The anophthalmia section im assuming is still part of genetic abnormalities and I would recommend starting with the genes which are affected – to create a flow on effect. Other than that it is well references and easy to read. In regards to your photo I would have a description of what the photo is about in the enlarged view to assist with the readers comprehension. Also, at what point can these abnormalities be detected in the womb – either from an ultrasound or from sampling of the genes or something - and does this have an affect on whether the mother keeps the child or not? I think the environmental causes of abnormalities are good and I would suggest that you add photos here to break up the text and also to give us an understanding of what happens.

Finally, your glossary needs a fair few more words in there as to help with our understanding. You have many references which is great, however take a loot at 46 – 49 – they all seem to be the same? It would be appropriate to merge them into one reference.

===Lab 9 ===

'''1. 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.'''

<pubmed>21490060</pubmed>

This research paper wanted to determine if Cdk4 has a role in embryonic pancreas development. The study required embryos being harvested from mice (Cdk4+/+, Cdk4–/– and Cdk4R24C) 1 hour after the discovery of the vaginal plug. The results indicated that Cdk4 is needed for growth and morphogenesis of the developing pancreas. Cdk4 deficiency decreases the size of the pancreas due to diminished mesenchyme development and less Pdx1+ cells. The results allude to the fact that Cdk4 promotes the Beta cell growth from the signalling transcription factor E2f1 to assist in the proliferation of Ngn3+endocrine precursors. Cdk4 thus is seen as an imperative regulator of the early developmental stages of the pancreas which regulates the growth of the endocrine precursors and pancreatic progenitors.

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

The teeth development necessitates the epithelial/ mesenchymal interaction between the ectoderm of the first pharyngeal arch along with ectomesenchymal cells of the neural crest . The tooth bud is the name given to the collection of cells which will later form a tooth <ref><pubmed>12615136</pubmed></ref>. There are 3 sections which contribute to the [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00019-9&isbn=978-1-4377-2002-0&uniqId=369704599-2#4-u1.0-B978-1-4377-2002-0..00019-9--s0055| developing teeth]:
# The enamel organ: The cells of the inner enamel epithelium of the enamel organ form the ameloblasts which differentiates and produces the enamel.
# The dental papilla: This is formed by the neural crest and cells from an unknown origin <ref><pubmed>21425080</pubmed></ref>. These cells develop into odontoblasts (or dentin forming cells). The mesenchymal cells contribute to the formation of the tooth pulp.
# The dental follicle: This produces 3 different cells. Cementoblasts create the cementum of the tooth. The osteoblasts create the alveolar bone around the tooth roots. Finally, the fibroblasts form the periodontal ligaments which attach the teeth to the alveolar bone.

Therefore, the ectoderm, neural crest and mesoderm all contribute to the development of the tooth.

===References===
<references/>

2012 Group Project 6

2012-10-04T23:54:13Z

Z3292017: /* Environmental */

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

==Introduction==

CAN YOU HEAR ME! – Hearing is one of the most important senses 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 and is inherent for both hunting and surviving. The sound energy produced has to be converted into an electrical signal for us to process this in our brain. For successful transmission the correct development of the ear is of utmost important. Not only the formation of the structures but also their correct assembly is imperative to normal ear functioning. In this project we will discuss the development of the human ear from implantation to birth by shining light on the differentiation of cells and signalling mechanisms that lead to normal development. We will then talk about some abnormal processes and mutations which lead to various structural and functional diseases. Technologies to detect and overcome these abnormalities will also be considered.

==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 was 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'''|| The labyrinth of the ear is discovered. <ref name="PMID11314703"><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 name="PMID11314703"/> [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.<ref name="PMID16269359"><pubmed>16269359</pubmed></ref> The Pinna or the auricle is designed such that the sound waves coming in get directed into the external auditory meatus (EAM). The waves travel through the EAM hit the tympanic membrane or eardrum, which causes it to vibrate.<ref name="PMID16269359"/> 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.<ref name="PMID16269359"/> <ref name="PMID11237469"><pubmed>11237469</pubmed></ref>

[[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.<ref name="PMID11237469"/> 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. <ref name="PMID16269359"/>

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.<ref name="PMID11237469"/> The bending of the cells causes them to activate which sends signals down the vestibulocochlear nerve.<ref name="PMID16269359"/> 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. <ref name="PMID16269359"/> <ref><pubmed>21774850</pubmed></ref>

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.<ref name="PMID16269359"/>

==Development==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px]]

The development of the outer and middle ear is attributed to the pharyngeal arches one and two. All the germ layer namely endoderm, mesoderm and ectoderm contribute to its formation. <ref><pubmed>8287791</pubmed></ref> The entire inner ear, as well as the neurons which innervate the sensory organ, are derived from the otic placode. <ref name="PMID17891709"><pubmed>17891709</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 and middle ear structures. 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. <ref><pubmed>11698185</pubmed></ref> 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.<ref name="PMID17891709"/> This will form an otic vesicle (otocyst) and further develop into the structures of the inner ear.

We will consider the outer, middle and inner ear separately.

===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 increases 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, then following with the others 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 have 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 splits in week 15, 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 name="PMID10976045"><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.

[[File: middle ear ossicles.png|left|thumb|250px|A view from inside the tympanic cavity of ''Lagenorhynchus obliquidens'' (Pacific White-sided Dolphin)]]

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 name="PMID10976045"/> <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.<ref name="PMID17891709"/>It is generally visible after gastrulation, once the first 5 to 10 pairs of somites have formed - week 3 of human embryonic development. Invagination occurs next, which creates the otocyst. Patterning occurs and as a result, we can see the start of formation of the cochlea during week 5. The otocyst 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"/> Chondrification and ossification of the otic capsule takes places from week 9 and week 11 respectively.[[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>
[[File:z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared]]

'''2''' ''Pre-otic field''

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"/>
[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]

'''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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|210px| Zebrafish otic vesicle]]

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'''
[[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''
[[File:semi-circular canals.jpg|thumb|300px| Wild-type semi-circular canal structure of zebrafish]]
It is also crucial for normal development of inner ear structures that Hedgehog signalling is repressed. <ref><pubmed>20223756</pubmed></ref>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them. <ref><pubmed>22778034</pubmed></ref>

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.<ref><pubmed>12530227</pubmed></ref> It exits through the internal acoustic meatus (IAM) to conduct signals to the brain for processing.

====Summary inner ear====

{| cellpadding=5 style="border:2px solid #00FF00"
|- bgcolor= #CCFF00
|'''SUMMARY OF THE INNER EAR DEVELOPMENT'''
|- 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 the 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.

* The semi-circular canals and the cochlea form as elongations of the otocyst, from the superior and inferior aspect respectively. The vestibulocochlear nerve is formed from cells lining the otocyst as well as cranial neural crest cells.
|}

==Abnormal Hearing==

In this section we will discuss with examples the different types of congenital abnormalities of the ear leading to hearing impairment or deafness. Apart from the Genetic section (whereby there are 5 ways the genes can be transferred), we will provide 3 examples in each due to the number of causes of congenital deafness. Note that the conditions can be split into syndromic and non syndromic along with conductive hearing loss and sensorineural hearing loss.

===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 name="PMID10980526"><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 name="PMID10980526"/>.
* 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>PMC3335728</pubmed></ref>.

|}

'''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
* Usher Syndrome predominantly affects the outer hair cells in the cochlear. Cochlear implants have given great improvements in both hearing and quality of life in these patients.
* 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 classic structural deformity is Mondini dysplasia of the cochlear whereby the cochlear is not complete having less than the required two and a half turns <ref><pubmed>3776519</pubmed></ref>.
* 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>.

||
[[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. It was also identified that 15 of the 23,000 pregnancies vertical transmission of the child contracting congenital toxoplasmosis <ref name="PMID3041362"><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* Detection of toxoplasmosis is achived through amniocentesis and subsequently using PCR to determine a positive result from DNA amplification <ref name="PMID3041362"/>.
* 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>. However inconclusive and inconsistent treatment investigations suggested to be caused by limited randomised controlled trials <ref><pubmed> 9988811 </pubmed></ref>.

|- bgcolor="#AAF0D1"
|''Rubella'' ||
* In 1979 an article provided evidence of the direct link between rubella and sensorineural deafness finding 24% of the hearing impaired children tested had the rubella antibody <ref><pubmed>84910</pubmed></ref>.
* Fetal infection risk will differ throughout the duration of the pregnancy. Week 1 to 10 has 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. There is a dramatic decrease in the second and third trimester (due to maternal antibodies and fetal cell mediated immune responses) however it goes back to 100% in the last month of pregnancy.
*Rubella infects the placenta via maternal viraemia which leads to necrotic areas in the chorionic villae epithelium <ref><pubmed>5949097</pubmed></ref>. It is thought that the rubella virus is passed through the fetal circulation via endothelial cell emboli. <ref><pubmed>2817948</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* It is an entirely preventable disease through the Rubella vaccine, being almost completely eliminated in western countries.

|- 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.
* Two 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 <ref><pubmed>3067168</pubmed></ref>
# 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''Drugs'''

{| cellpadding=5 style="border:1px solid #FF0090"
|- bgcolor="#FF55A3"
|'''Drug'''||'''Description'''
|- bgcolor="#FFF0F5"
|''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 <ref name="PMID9161611"><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 greater amount of apoptosis during the inner ear development and thus decreased growth of neurons and myelin and subsequently the synapses. Intermittent conductive hearing loss is thought to be due to poorly formed eustachian tube <ref><pubmed>12795509</pubmed></ref>.
* The central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing <ref name="PMID9161611"/>.

|- bgcolor="#FFA6C9"
|''Isotretinoin'' ||
* Isotretinoin is a treatment option for patients with severe cystic acne.
* It is teratogenic and its associated congenital malformations include: Lack of ears and malformations of the inner, middle and outer ears, along with mental retardations, facial malformations and heart and limb defects. <ref><pubmed>PMC1859978</pubmed></ref>.
* This is thought to be due to the ear not reaching full development such as the Mondini malformation.
* The most severe inner ear abnormalities occur when the mother was taking isotretinoin during the gastrulation stage, with the abnormalities indicating that the development was interrupted. It is thought that this is due to the disruption of the neural crest cell population. <ref><pubmed>1440418</pubmed></ref>

|- bgcolor="#FFF0F5"
|''Thalidomide'' ||
* Thalidomide was a drug used to ease morning sickness symptoms in the 1950's and 1960's until it was found to be teratogenic.
* Known for its limb reduction abnormalities, it also contributes to outer and inner ear malformations and heart and eye defects.
* Critical time periods for exposure to Thalidomide for outer ear malformations was days 20-24 post fertilisation and inner ear from day 24-34.
* Thalidomide is thought to increase the oxygen radical formation which generates oxidative stress along with inhibiting angiogenesis <ref><pubmed>21507989</pubmed></ref>.
|}

===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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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 - Auditory Brainstem Response test]]

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===
[[File:Hearing_aids.JPG|thumb|200 px|right| 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 amplification 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 amplification 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 amplifier. The amplifier sends the impulses though the speaker into the ear as an increased sound.
<ref>National Institute of Health, '''Hearing Aid Basics''', http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx, Access date 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>6028666</pubmed></ref>

[[File:Cochlear_Implant.jpg|x250px|Cochlear Implant]]

==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==

*'''Chondrification''': the process that results in the formation of cartilage

*'''Cranial''': towards the head of the embryo

*'''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

*'''FGF – Fibroblast Growth Factor''': a family of polypeptides that are involved in embryonic development and function as growth and differentiation factors.

*'''Foxi2''': forkhead box I2 gene. Located on chromosome 10, position 26.2, this gene produces a transcription factor protein, which regulates the activity of other genes

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

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

*'''Incus''': the second ossicle of the middle ear, located between the malleus and stapes

*'''Invagination''': the infolding of tissue, such as the otic placode

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

*'''Malleus''': the first ossicle of the middle ear, located between the tympanic membrane and the incus

*'''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

*'''Nonsyndromic deafness''': Hearing impairment not affiliated with other signs or symptoms

*'''Notch''': this receptor allows for binding of particular ligands and hence enables signalling between neighbouring cells.

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

*'''Ossification''': the process that results in the formation of bone

*'''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

*'''Paraxial mesoderm''': The mesoderm located alongside the neural tube

*'''Pax2''': the paired box 2 gene. Located on chromosome 10, position 24, this gene produces a transcription factor protein, which regulates the activity of other genes

*'''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

*'''Sox1''': SRY (sex determining region Y)-box 1. Located on chromosome 13, position 32, this gene produces a transcription factor protein and is mainly expressed in the developing central nervous system.

*'''Sox2''': SRY (sex determining region Y)-box 2. Located on chromosome 3, position 26.33, this gene produces a transcription factor protein. It is needed for embryonic stem cell pluripotency and neural stem cell self-renewal.

*'''Sox3''': SRY (sex determining region Y)-box 3. Located on chromosome 3, position 26.33, this gene produces a transcription factor protein. Needed to maintain undifferentiated neural cells, formation of the hypothalamo-pituitary axis and sex differentiation.

*'''Stapes''': the third ossicle of the middle ear, located between the incus and the oval window

*'''Syndromic deafness''': Hearing impairment occurring with additional abnormalities in the body

*'''Topological organisation''': the organisation of an area, such as the otocyst, according to the structures it relates to, such as the semicircular canals and the cochlea.

*'''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

*'''Wnt signaling molecules''': a highly conserved family of proteins that control interactions between cells

Please note, to ensure the accuracy of the descriptions of terms above, various dictionaries were used, including [http://medical-dictionary.thefreedictionary.com the medical dictionary] and [http://www.britannica.com the Britannica online encyclopedia].

== References ==
<references/>

==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]

{{External Links}}

==Image Gallery==

<gallery>

Image: Z3333865.Ruby.jpeg|EARS
Image: Anatomy_of_the_Ear.JPG|Anatomy of the ear
Image: Histology_of_Inner_Ear.png|Histology of Inner Ear
Image: Pharyngeal_arch_one_and_two_in_mice.png|Pharyngeal arches one and two in mice embryo
Image: Devt_of_external_ear.JPG|The image depicts the development of the pinna through the fetal development stages
Image: middle ear ossicles.png|A view from inside the tympanic cavity of ''Lagenorhynchus obliquidens'' (Pacific White-sided Dolphin)
Image: normal cochlea.png |Wild-type inner ear showing normal morphology
Image: z3333865.pax2 and 8.jpg|Early expression of Pax2 and Pax8 compared
Image: otic placode embryo.jpg|Otic placode of an embryo
Image: neural fate.jpg|Recent model related to sensory fate.
Image: otic vesicle.jpg|Zebrafish otic vesicle
Image: z3333865.gene expression.jpeg|Representative expression patterns of genes controlling cochlear and vestibular specification.
Image: semi-circular canals.jpg|Wild-type semi-circular canal structure of zebrafish
Image: cochlea stereocilia bundle.jpg|Stereocilia bundles in the normal cochlea
Image: Mutation on GJB2 gene.jpg|Mutation on GJB2 gene
Image: Dominant_diagram.jpg|Dominant Inheritance
Image: Autosomal_Recessive_Inheritance_Diagram.jpg|Autosomal Recessive inheritance
Image: X_Linked_Recessive_Diagram.jpg|X-linked Recessive inheritance
Image: Basal Cochlear Outer Hair Cells.jpg| Scanning electron microscopy, showing hair cells of the basal and middle cochlea
Image: Pendred_Syndrome_Showing_Mondini_Defects.jpg|Pendred Syndrome
Image: MRI_of_Goldenhar_Syndrome.jpg|Goldenhar Syndrome
Image: Bilateral_Stenosis_of_Internal_Auditory_canal.jpg|Bilateral Stenosis of Internal Auditory Canal
Image: Enlarged_Vestibular_aqueduct.jpg|Enlarged Vestibular Aqueduct
Image: Microtia_boy_surgery.jpg|Microtia
Image: Infant hearing test.jpg|Testing the hearing of an infant - Auditory Brainstem Response test
Image: Hearing aids.JPG| Behind-the-ear (BTE), in-the-ear (ITE), in-the-canal (ITC), and completely-in-canal (CIC) hearing aids
Image: Cochlear_Implant.jpg|Cochlear Implant
Image: Atoh1 model.png|Atoh1-cre is expressed in hair cells and causes transient limited expression of Atoh1 in CKO ears
Image: Atoh1 hair cell loss.png|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.
Image: Aquaporins.png | Aquaporins 1, 4, and 5 in the inner ear (A-C) and middle ear (D-G) – staining by AQP. H: KCNJ10 also stained the middle ear epithelium. Negative controls are displayed as inset pictures

</gallery>

--[[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

2012-10-04T23:49:45Z

Z3292017:

2012 Group Project 6

2012-10-04T23:23:41Z

Z3292017: /* Outer Ear */

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

==Introduction==

CAN YOU HEAR ME! – Hearing is one of the most important senses 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 and is inherent for both hunting and surviving. The sound energy produced has to be converted into an electrical signal for us to process this in our brain. For successful transmission the correct development of the ear is of utmost important. Not only the formation of the structures but also their correct assembly is imperative to normal ear functioning. In this project we will discuss the development of the human ear from implantation to birth by shining light on the differentiation of cells and signalling mechanisms that lead to normal development. We will then talk about some abnormal processes and mutations which lead to various structural and functional diseases. Technologies to detect and overcome these abnormalities will also be considered.

==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 was 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'''|| The labyrinth of the ear is discovered. <ref name="PMID11314703"><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 name="PMID11314703"/> [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 (EAM). 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. <ref name="PMID16269359"><pubmed>16269359</pubmed></ref> <ref><pubmed>11237469</pubmed></ref>

[[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. <ref name="PMID16269359"/>

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. <ref name="PMID16269359"/> <ref><pubmed>21774850</pubmed></ref>

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==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px]]

The development of the outer and middle ear is attributed to the pharyngeal arches one and two. All the germ layer namely endoderm, mesoderm and ectoderm contribute to its formation. <ref><pubmed>8287791</pubmed></ref> The entire inner ear, as well as the neurons which innervate the sensory organ, are derived from the otic placode. <ref name="PMID17891709"><pubmed>17891709</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 and middle ear structures. 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. <ref><pubmed>11698185</pubmed></ref> 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.<ref name="PMID17891709"/> This will form an otic vesicle (otocyst) and further develop into the structures of the inner ear.

We will consider the outer, middle and inner ear separately.

===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 increases 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, then following with the others 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 have 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 splits in week 15, 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 name="PMID10976045"><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.

[[File: middle ear ossicles.png|left|thumb|250px|A view from inside the tympanic cavity of ''Lagenorhynchus obliquidens'' (Pacific White-sided Dolphin)]]

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 name="PMID10976045"/> <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.<ref name="PMID17891709"/>It is generally visible after gastrulation, once the first 5 to 10 pairs of somites have formed - week 3 of human embryonic development. Invagination occurs next, which creates the otocyst. Patterning occurs and as a result, we can see the start of formation of the cochlea during week 5. The otocyst 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"/> Chondrification and ossification of the otic capsule takes places from week 9 and week 11 respectively.[[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>
[[File:z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared]]

'''2''' ''Pre-otic field''

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"/>
[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]

'''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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|210px| Zebrafish otic vesicle]]

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'''
[[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''
[[File:semi-circular canals.jpg|thumb|300px| Wild-type semi-circular canal structure of zebrafish]]
It is also crucial for normal development of inner ear structures that Hedgehog signalling is repressed. <ref><pubmed>20223756</pubmed></ref>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them. <ref><pubmed>22778034</pubmed></ref>

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.<ref><pubmed>12530227</pubmed></ref> It exits through the internal acoustic meatus (IAM) to conduct signals to the brain for processing.

====Summary inner ear====

{| cellpadding=5 style="border:2px solid #00FF00"
|- bgcolor= #CCFF00
|'''SUMMARY OF THE INNER EAR DEVELOPMENT'''
|- 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 the 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.

* The semi-circular canals and the cochlea form as elongations of the otocyst, from the superior and inferior aspect respectively. The vestibulocochlear nerve is formed from cells lining the otocyst as well as cranial neural crest cells.
|}

==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 name="PMID10980526"><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 name="PMID10980526"/>.
* 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>PMC3335728</pubmed></ref>.

|}

'''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
* Usher Syndrome predominantly affects the outer hair cells in the cochlear. Cochlear implants have given great improvements in both hearing and quality of life in these patients.
* 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 classic structural deformity is Mondini dysplasia of the cochlear whereby the cochlear is not complete having less than the required two and a half turns <ref><pubmed>3776519</pubmed></ref>.
* 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>.

||
[[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. It was also identified that 15 of the 23,000 pregnancies vertical transmission of the child contracting congenital toxoplasmosis <ref name="PMID3041362"><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* Detection of toxoplasmosis is achived through amniocentesis and subsequently using PCR to determine a positive result from DNA amplification <ref name="PMID3041362"/>.
* 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>. However inconclusive and inconsistent treatment investigations suggested to be caused by limited randomised controlled trials <ref><pubmed> 9988811 </pubmed></ref>.

|- bgcolor="#AAF0D1"
|''Rubella'' ||
* In 1979 an article provided evidence of the direct link between rubella and sensorineural deafness finding 24% of the hearing impaired children tested had the rubella antibody <ref><pubmed>84910</pubmed></ref>.
* Fetal infection risk will differ throughout the duration of the pregnancy. Week 1 to 10 has 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. There is a dramatic decrease in the second and third trimester (due to maternal antibodies and fetal cell mediated immune responses) however it goes back to 100% in the last month of pregnancy.
*Rubella infects the placenta via maternal viraemia which leads to necrotic areas in the chorionic villae epithelium <ref><pubmed>5949097</pubmed></ref>. It is thought that the rubella virus is passed through the fetal circulation via endothelial cell emboli. <ref><pubmed>2817948</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* It is an entirely preventable disease through the Rubella vaccine, being almost completely eliminated in western countries.

|- 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.
* Two 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 <ref><pubmed>3067168</pubmed></ref>
# 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''Drugs'''

{| cellpadding=5 style="border:1px solid #FF0090"
|- bgcolor="#FF55A3"
|'''Drug'''||'''Description'''
|- bgcolor="#FFF0F5"
|''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 <ref name="PMID9161611"><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 greater amount of apoptosis during the inner ear development and thus decreased growth of neurons and myelin and subsequently the synapses. Intermittent conductive hearing loss is thought to be due to poorly formed eustachian tube <ref><pubmed>12795509</pubmed></ref>.
* The central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing <ref name="PMID9161611"/>.

|- bgcolor="#FFA6C9"
|''Isotretinoin'' ||
* Isotretinoin is a treatment option for patients with severe cystic acne.
* It is teratogenic and its associated congenital malformations include: Lack of ears and malformations of the inner, middle and outer ears, along with mental retardations, facial malformations and heart and limb defects. <ref><pubmed>PMC1859978</pubmed></ref>.
* This is thought to be due to the ear not reaching full development such as the Mondini malformation.
* The most severe inner ear abnormalities occur when the mother was taking isotretinoin during the gastrulation stage, with the abnormalities indicating that the development was interrupted. It is thought that this is due to the disruption of the neural crest cell population. <ref><pubmed>1440418</pubmed></ref>

|- bgcolor="#FFF0F5"
|''Thalidomide'' ||
* Thalidomide was a drug used to ease morning sickness symptoms in the 1950's and 1960's until it was found to be teratogenic.
* Known for its limb reduction abnormalities, it also contributes to outer and inner ear malformations and heart and eye defects.
* Critical time periods for exposure to Thalidomide for outer ear malformations was days 20-24 post fertilisation and inner ear from day 24-34.
* Thalidomide is thought to increase the oxygen radical formation which generates oxidative stress along with inhibiting angiogenesis <ref><pubmed>21507989</pubmed></ref>.
|}

===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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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 - Auditory Brainstem Response test]]

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===
[[File:Hearing_aids.JPG|thumb|200 px|right| 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 amplification 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 amplification 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 amplifier. The amplifier sends the impulses though the speaker into the ear as an increased sound.
<ref>National Institute of Health, '''Hearing Aid Basics''', http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx, Access date 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>6028666</pubmed></ref>

[[File:Cochlear_Implant.jpg|x250px|Cochlear Implant]]

==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

*'''Nonsyndromic deafness''': Hearing impairment not affiliated with other signs or symptoms

*'''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

*'''Syndromic deafness''': Hearing impairment occurring with additional abnormalities in the body

*'''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

== References ==
<references/>

==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]

{{External Links}}

==Image Gallery==

<gallery>

Image: Z3333865.Ruby.jpeg|EARS
Image: Anatomy_of_the_Ear.JPG|Anatomy of the ear
Image: Histology_of_Inner_Ear.png|Histology of Inner Ear
Image: Pharyngeal_arch_one_and_two_in_mice.png|Pharyngeal arches one and two in mice embryo
Image: Devt_of_external_ear.JPG|The image depicts the development of the pinna through the fetal development stages
Image: middle ear ossicles.png|A view from inside the tympanic cavity of ''Lagenorhynchus obliquidens'' (Pacific White-sided Dolphin)
Image: normal cochlea.png |Wild-type inner ear showing normal morphology
Image: z3333865.pax2 and 8.jpg|Early expression of Pax2 and Pax8 compared
Image: otic placode embryo.jpg|Otic placode of an embryo
Image: neural fate.jpg|Recent model related to sensory fate.
Image: otic vesicle.jpg|Zebrafish otic vesicle
Image: z3333865.gene expression.jpeg|Representative expression patterns of genes controlling cochlear and vestibular specification.
Image: semi-circular canals.jpg|Wild-type semi-circular canal structure of zebrafish
Image: cochlea stereocilia bundle.jpg|Stereocilia bundles in the normal cochlea
Image: Mutation on GJB2 gene.jpg|Mutation on GJB2 gene
Image: Dominant_diagram.jpg|Dominant Inheritance
Image: Autosomal_Recessive_Inheritance_Diagram.jpg|Autosomal Recessive inheritance
Image: X_Linked_Recessive_Diagram.jpg|X-linked Recessive inheritance
Image: Basal Cochlear Outer Hair Cells.jpg| Scanning electron microscopy, showing hair cells of the basal and middle cochlea
Image: Pendred_Syndrome_Showing_Mondini_Defects.jpg|Pendred Syndrome
Image: MRI_of_Goldenhar_Syndrome.jpg|Goldenhar Syndrome
Image: Bilateral_Stenosis_of_Internal_Auditory_canal.jpg|Bilateral Stenosis of Internal Auditory Canal
Image: Enlarged_Vestibular_aqueduct.jpg|Enlarged Vestibular Aqueduct
Image: Microtia_boy_surgery.jpg|Microtia
Image: Infant hearing test.jpg|Testing the hearing of an infant - Auditory Brainstem Response test
Image: Hearing aids.JPG| Behind-the-ear (BTE), in-the-ear (ITE), in-the-canal (ITC), and completely-in-canal (CIC) hearing aids
Image: Cochlear_Implant.jpg|Cochlear Implant
Image: Atoh1 model.png|Atoh1-cre is expressed in hair cells and causes transient limited expression of Atoh1 in CKO ears
Image: Atoh1 hair cell loss.png|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.
Image: Aquaporins.png | Aquaporins 1, 4, and 5 in the inner ear (A-C) and middle ear (D-G) – staining by AQP. H: KCNJ10 also stained the middle ear epithelium. Negative controls are displayed as inset pictures

</gallery>

--[[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

2012-10-04T23:08:04Z

Z3292017: /* 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 senses 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 and is inherent for both hunting and surviving. The sound energy produced has to be converted into an electrical signal for us to process this in our brain. For successful transmission the correct development of the ear is of utmost important. Not only the formation of the structures but also their correct assembly is imperative to normal ear functioning. In this project we will discuss the development of the human ear from implantation to birth by shining light on the differentiation of cells and signalling mechanisms that lead to normal development. We will then talk about some abnormal processes and mutations which lead to various structural and functional diseases. Technologies to detect and overcome these abnormalities will also be considered.

==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 was 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'''|| The labyrinth of the ear is discovered. <ref name="PMID11314703"><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 name="PMID11314703"/> [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 (EAM). 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. <ref name="PMID16269359"><pubmed>16269359</pubmed></ref> <ref><pubmed>11237469</pubmed></ref>

[[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. <ref name="PMID16269359"/>

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. <ref name="PMID16269359"/> <ref><pubmed>21774850</pubmed></ref>

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==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px]]

The development of the outer and middle ear is attributed to the pharyngeal arches one and two. All the germ layer namely endoderm, mesoderm and ectoderm contribute to its formation. <ref><pubmed>8287791</pubmed></ref> The entire inner ear, as well as the neurons which innervate the sensory organ, are derived from the otic placode. <ref name="PMID17891709"><pubmed>17891709</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 and middle ear structures. 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. <ref><pubmed>11698185</pubmed></ref> 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.<ref name="PMID17891709"/> This will form an otic vesicle (otocyst) and further develop into the structures of the inner ear.

We will consider the outer, middle and inner ear separately.

===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 increases 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, then following with the others 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 splits in week 15, 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 name="PMID10976045"><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.

[[File: middle ear ossicles.png|left|thumb|250px|A view from inside the tympanic cavity of ''Lagenorhynchus obliquidens'' (Pacific White-sided Dolphin)]]

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 name="PMID10976045"/> <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.<ref name="PMID17891709"/>It is generally visible after gastrulation, once the first 5 to 10 pairs of somites have formed - week 3 of human embryonic development. Invagination occurs next, which creates the otocyst. Patterning occurs and as a result, we can see the start of formation of the cochlea during week 5. The otocyst 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"/> Chondrification and ossification of the otic capsule takes places from week 9 and week 11 respectively.[[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>
[[File:z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared]]

'''2''' ''Pre-otic field''

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"/>
[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]

'''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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|210px| Zebrafish otic vesicle]]

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'''
[[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''
[[File:semi-circular canals.jpg|thumb|300px| Wild-type semi-circular canal structure of zebrafish]]
It is also crucial for normal development of inner ear structures that Hedgehog signalling is repressed. <ref><pubmed>20223756</pubmed></ref>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them. <ref><pubmed>22778034</pubmed></ref>

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.<ref><pubmed>12530227</pubmed></ref> It exits through the internal acoustic meatus (IAM) to conduct signals to the brain for processing.

====Summary inner ear====

{| cellpadding=5 style="border:2px solid #00FF00"
|- bgcolor= #CCFF00
|'''SUMMARY OF THE INNER EAR DEVELOPMENT'''
|- 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 the 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.

* The semi-circular canals and the cochlea form as elongations of the otocyst, from the superior and inferior aspect respectively. The vestibulocochlear nerve is formed from cells lining the otocyst as well as cranial neural crest cells.
|}

==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 name="PMID10980526"><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 name="PMID10980526"/>.
* 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>PMC3335728</pubmed></ref>.

|}

'''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
* Usher Syndrome predominantly affects the outer hair cells in the cochlear. Cochlear implants have given great improvements in both hearing and quality of life in these patients.
* 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 classic structural deformity is Mondini dysplasia of the cochlear whereby the cochlear is not complete having less than the required two and a half turns <ref><pubmed>3776519</pubmed></ref>.
* 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>.

||
[[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. It was also identified that 15 of the 23,000 pregnancies vertical transmission of the child contracting congenital toxoplasmosis <ref name="PMID3041362"><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* Detection of toxoplasmosis is achived through amniocentesis and subsequently using PCR to determine a positive result from DNA amplification <ref name="PMID3041362"/>.
* 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>. However inconclusive and inconsistent treatment investigations suggested to be caused by limited randomised controlled trials <ref><pubmed> 9988811 </pubmed></ref>.

|- bgcolor="#AAF0D1"
|''Rubella'' ||
* In 1979 an article provided evidence of the direct link between rubella and sensorineural deafness finding 24% of the hearing impaired children tested had the rubella antibody <ref><pubmed>84910</pubmed></ref>.
* Fetal infection risk will differ throughout the duration of the pregnancy. Week 1 to 10 has 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. There is a dramatic decrease in the second and third trimester (due to maternal antibodies and fetal cell mediated immune responses) however it goes back to 100% in the last month of pregnancy.
*Rubella infects the placenta via maternal viraemia which leads to necrotic areas in the chorionic villae epithelium <ref><pubmed>5949097</pubmed></ref>. It is thought that the rubella virus is passed through the fetal circulation via endothelial cell emboli. <ref><pubmed>2817948</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* It is an entirely preventable disease through the Rubella vaccine, being almost completely eliminated in western countries.

|- 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.
* Two 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 <ref><pubmed>3067168</pubmed></ref>
# 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''Drugs'''

{| cellpadding=5 style="border:1px solid #FF0090"
|- bgcolor="#FF55A3"
|'''Drug'''||'''Description'''
|- bgcolor="#FFF0F5"
|''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 <ref name="PMID9161611"><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 greater amount of apoptosis during the inner ear development and thus decreased growth of neurons and myelin and subsequently the synapses. Intermittent conductive hearing loss is thought to be due to poorly formed eustachian tube <ref><pubmed>12795509</pubmed></ref>.
* The central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing <ref name="PMID9161611"/>.

|- bgcolor="#FFA6C9"
|''Isotretinoin'' ||
* Isotretinoin is a treatment option for patients with severe cystic acne.
* It is teratogenic and its associated congenital malformations include: Lack of ears and malformations of the inner, middle and outer ears, along with mental retardations, facial malformations and heart and limb defects. <ref><pubmed>PMC1859978</pubmed></ref>.
* This is thought to be due to the ear not reaching full development such as the Mondini malformation.
* The most severe inner ear abnormalities occur when the mother was taking isotretinoin during the gastrulation stage, with the abnormalities indicating that the development was interrupted. It is thought that this is due to the disruption of the neural crest cell population. <ref><pubmed>1440418</pubmed></ref>

|- bgcolor="#FFF0F5"
|''Thalidomide'' ||
* Thalidomide was a drug used to ease morning sickness symptoms in the 1950's and 1960's until it was found to be teratogenic.
* Known for its limb reduction abnormalities, it also contributes to outer and inner ear malformations and heart and eye defects.
* Critical time periods for exposure to Thalidomide for outer ear malformations was days 20-24 post fertilisation and inner ear from day 24-34.
* Thalidomide is thought to increase the oxygen radical formation which generates oxidative stress along with inhibiting angiogenesis <ref><pubmed>21507989</pubmed></ref>.
|}

===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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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 - Auditory Brainstem Response test]]

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===
[[File:Hearing_aids.JPG|thumb|200 px|right| 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 amplification 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 amplification 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 amplifier. The amplifier sends the impulses though the speaker into the ear as an increased sound.
<ref>National Institute of Health, '''Hearing Aid Basics''', http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx, Access date 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>6028666</pubmed></ref>

[[File:Cochlear_Implant.jpg|x250px|Cochlear Implant]]

==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

*'''Nonsyndromic deafness''': Hearing impairment not affiliated with other signs or symptoms

*'''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

*'''Syndromic deafness''': Hearing impairment occurring with additional abnormalities in the body

*'''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

== References ==
<references/>

==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]

{{External Links}}

==Image Gallery==

<gallery>

Image: Z3333865.Ruby.jpeg|EARS
Image: Anatomy_of_the_Ear.JPG|Anatomy of the ear
Image: Histology_of_Inner_Ear.png|Histology of Inner Ear
Image: Pharyngeal_arch_one_and_two_in_mice.png|Pharyngeal arches one and two in mice embryo
Image: Devt_of_external_ear.JPG|The image depicts the development of the pinna through the fetal development stages
Image: middle ear ossicles.png|A view from inside the tympanic cavity of ''Lagenorhynchus obliquidens'' (Pacific White-sided Dolphin)
Image: normal cochlea.png |Wild-type inner ear showing normal morphology
Image: z3333865.pax2 and 8.jpg|Early expression of Pax2 and Pax8 compared
Image: otic placode embryo.jpg|Otic placode of an embryo
Image: neural fate.jpg|Recent model related to sensory fate.
Image: otic vesicle.jpg|Zebrafish otic vesicle
Image: z3333865.gene expression.jpeg|Representative expression patterns of genes controlling cochlear and vestibular specification.
Image: semi-circular canals.jpg|Wild-type semi-circular canal structure of zebrafish
Image: cochlea stereocilia bundle.jpg|Stereocilia bundles in the normal cochlea
Image: Mutation on GJB2 gene.jpg|Mutation on GJB2 gene
Image: Dominant_diagram.jpg|Dominant Inheritance
Image: Autosomal_Recessive_Inheritance_Diagram.jpg|Autosomal Recessive inheritance
Image: X_Linked_Recessive_Diagram.jpg|X-linked Recessive inheritance
Image: Basal Cochlear Outer Hair Cells.jpg| Scanning electron microscopy, showing hair cells of the basal and middle cochlea
Image: Pendred_Syndrome_Showing_Mondini_Defects.jpg|Pendred Syndrome
Image: MRI_of_Goldenhar_Syndrome.jpg|Goldenhar Syndrome
Image: Bilateral_Stenosis_of_Internal_Auditory_canal.jpg|Bilateral Stenosis of Internal Auditory Canal
Image: Enlarged_Vestibular_aqueduct.jpg|Enlarged Vestibular Aqueduct
Image: Microtia_boy_surgery.jpg|Microtia
Image: Infant hearing test.jpg|Testing the hearing of an infant - Auditory Brainstem Response test
Image: Hearing aids.JPG| Behind-the-ear (BTE), in-the-ear (ITE), in-the-canal (ITC), and completely-in-canal (CIC) hearing aids
Image: Cochlear_Implant.jpg|Cochlear Implant
Image: Atoh1 model.png|Atoh1-cre is expressed in hair cells and causes transient limited expression of Atoh1 in CKO ears
Image: Atoh1 hair cell loss.png|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.
Image: Aquaporins.png | Aquaporins 1, 4, and 5 in the inner ear (A-C) and middle ear (D-G) – staining by AQP. H: KCNJ10 also stained the middle ear epithelium. Negative controls are displayed as inset pictures

</gallery>

--[[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

2012-10-04T23:02:11Z

Z3292017: /* Cochlea Ear Implant */

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

==Introduction==

CAN YOU HEAR ME! – Hearing is one of the most important senses 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 and is inherent for both hunting and surviving. The sound energy produced has to be converted into an electrical signal for us to process this in our brain. For successful transmission the correct development of the ear is of utmost important. Not only the formation of the structures but also their correct assembly is imperative to normal ear functioning. In this project we will discuss the development of the human ear from implantation to birth by shining light on the differentiation of cells and signalling mechanisms that lead to normal development. We will then talk about some abnormal processes and mutations which lead to various structural and functional diseases. Technologies to detect and overcome these abnormalities will also be considered.

==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 was 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'''|| The labyrinth of the ear is discovered. <ref name="PMID11314703"><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 name="PMID11314703"/> [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. <ref name="PMID16269359"><pubmed>16269359</pubmed></ref> <ref><pubmed>11237469</pubmed></ref>

[[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. <ref name="PMID16269359"/>

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. <ref name="PMID16269359"/> <ref><pubmed>21774850</pubmed></ref>

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==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px]]

The development of the outer and middle ear is attributed to the pharyngeal arches one and two. All the germ layer namely endoderm, mesoderm and ectoderm contribute to its formation. <ref><pubmed>8287791</pubmed></ref> The entire inner ear, as well as the neurons which innervate the sensory organ, are derived from the otic placode. <ref name="PMID17891709"><pubmed>17891709</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 and middle ear structures. 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. <ref><pubmed>11698185</pubmed></ref> 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.<ref name="PMID17891709"/> This will form an otic vesicle (otocyst) and further develop into the structures of the inner ear.

We will consider the outer, middle and inner ear separately.

===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 increases 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, then following with the others 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 splits in week 15, 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 name="PMID10976045"><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.

[[File: middle ear ossicles.png|left|thumb|250px|A view from inside the tympanic cavity of ''Lagenorhynchus obliquidens'' (Pacific White-sided Dolphin)]]

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 name="PMID10976045"/> <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.<ref name="PMID17891709"/>It is generally visible after gastrulation, once the first 5 to 10 pairs of somites have formed - week 3 of human embryonic development. Invagination occurs next, which creates the otocyst. Patterning occurs and as a result, we can see the start of formation of the cochlea during week 5. The otocyst 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"/> Chondrification and ossification of the otic capsule takes places from week 9 and week 11 respectively.[[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>
[[File:z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared]]

'''2''' ''Pre-otic field''

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"/>
[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]

'''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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|210px| Zebrafish otic vesicle]]

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'''
[[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''
[[File:semi-circular canals.jpg|thumb|300px| Wild-type semi-circular canal structure of zebrafish]]
It is also crucial for normal development of inner ear structures that Hedgehog signalling is repressed. <ref><pubmed>20223756</pubmed></ref>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them. <ref><pubmed>22778034</pubmed></ref>

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.<ref><pubmed>12530227</pubmed></ref> It exits through the internal acoustic meatus (IAM) to conduct signals to the brain for processing.

====Summary inner ear====

{| cellpadding=5 style="border:2px solid #00FF00"
|- bgcolor= #CCFF00
|'''SUMMARY OF THE INNER EAR DEVELOPMENT'''
|- 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 the 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.

* The semi-circular canals and the cochlea form as elongations of the otocyst, from the superior and inferior aspect respectively. The vestibulocochlear nerve is formed from cells lining the otocyst as well as cranial neural crest cells.
|}

==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 name="PMID10980526"><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 name="PMID10980526"/>.
* 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>PMC3335728</pubmed></ref>.

|}

'''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
* Usher Syndrome predominantly affects the outer hair cells in the cochlear. Cochlear implants have given great improvements in both hearing and quality of life in these patients.
* 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 classic structural deformity is Mondini dysplasia of the cochlear whereby the cochlear is not complete having less than the required two and a half turns <ref><pubmed>3776519</pubmed></ref>.
* 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>.

||
[[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. It was also identified that 15 of the 23,000 pregnancies vertical transmission of the child contracting congenital toxoplasmosis <ref name="PMID3041362"><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* Detection of toxoplasmosis is achived through amniocentesis and subsequently using PCR to determine a positive result from DNA amplification <ref name="PMID3041362"/>.
* 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>. However inconclusive and inconsistent treatment investigations suggested to be caused by limited randomised controlled trials <ref><pubmed> 9988811 </pubmed></ref>.

|- bgcolor="#AAF0D1"
|''Rubella'' ||
* In 1979 an article provided evidence of the direct link between rubella and sensorineural deafness finding 24% of the hearing impaired children tested had the rubella antibody <ref><pubmed>84910</pubmed></ref>.
* Fetal infection risk will differ throughout the duration of the pregnancy. Week 1 to 10 has 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. There is a dramatic decrease in the second and third trimester (due to maternal antibodies and fetal cell mediated immune responses) however it goes back to 100% in the last month of pregnancy.
*Rubella infects the placenta via maternal viraemia which leads to necrotic areas in the chorionic villae epithelium <ref><pubmed>5949097</pubmed></ref>. It is thought that the rubella virus is passed through the fetal circulation via endothelial cell emboli. <ref><pubmed>2817948</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* It is an entirely preventable disease through the Rubella vaccine, being almost completely eliminated in western countries.

|- 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.
* Two 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 <ref><pubmed>3067168</pubmed></ref>
# 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''Drugs'''

{| cellpadding=5 style="border:1px solid #FF0090"
|- bgcolor="#FF55A3"
|'''Drug'''||'''Description'''
|- bgcolor="#FFF0F5"
|''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 <ref name="PMID9161611"><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 greater amount of apoptosis during the inner ear development and thus decreased growth of neurons and myelin and subsequently the synapses. Intermittent conductive hearing loss is thought to be due to poorly formed eustachian tube <ref><pubmed>12795509</pubmed></ref>.
* The central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing <ref name="PMID9161611"/>.

|- bgcolor="#FFA6C9"
|''Isotretinoin'' ||
* Isotretinoin is a treatment option for patients with severe cystic acne.
* It is teratogenic and its associated congenital malformations include: Lack of ears and malformations of the inner, middle and outer ears, along with mental retardations, facial malformations and heart and limb defects. <ref><pubmed>PMC1859978</pubmed></ref>.
* This is thought to be due to the ear not reaching full development such as the Mondini malformation.
* The most severe inner ear abnormalities occur when the mother was taking isotretinoin during the gastrulation stage, with the abnormalities indicating that the development was interrupted. It is thought that this is due to the disruption of the neural crest cell population. <ref><pubmed>1440418</pubmed></ref>

|- bgcolor="#FFF0F5"
|''Thalidomide'' ||
* Thalidomide was a drug used to ease morning sickness symptoms in the 1950's and 1960's until it was found to be teratogenic.
* Known for its limb reduction abnormalities, it also contributes to outer and inner ear malformations and heart and eye defects.
* Critical time periods for exposure to Thalidomide for outer ear malformations was days 20-24 post fertilisation and inner ear from day 24-34.
* Thalidomide is thought to increase the oxygen radical formation which generates oxidative stress along with inhibiting angiogenesis <ref><pubmed>21507989</pubmed></ref>.
|}

===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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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 - Auditory Brainstem Response test]]

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===
[[File:Hearing_aids.JPG|thumb|200 px|right| 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 amplification 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 amplification 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 amplifier. The amplifier sends the impulses though the speaker into the ear as an increased sound.
<ref>National Institute of Health, '''Hearing Aid Basics''', http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx, Access date 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>6028666</pubmed></ref>

[[File:Cochlear_Implant.jpg|x250px|Cochlear Implant]]

==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

*'''Nonsyndromic deafness''': Hearing impairment not affiliated with other signs or symptoms

*'''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

*'''Syndromic deafness''': Hearing impairment occurring with additional abnormalities in the body

*'''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

== References ==
<references/>

==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]

{{External Links}}

==Image Gallery==

<gallery>

Image: Z3333865.Ruby.jpeg|EARS
Image: Anatomy_of_the_Ear.JPG|Anatomy of the ear
Image: Histology_of_Inner_Ear.png|Histology of Inner Ear
Image: Pharyngeal_arch_one_and_two_in_mice.png|Pharyngeal arches one and two in mice embryo
Image: Devt_of_external_ear.JPG|The image depicts the development of the pinna through the fetal development stages
Image: middle ear ossicles.png|A view from inside the tympanic cavity of ''Lagenorhynchus obliquidens'' (Pacific White-sided Dolphin)
Image: normal cochlea.png |Wild-type inner ear showing normal morphology
Image: z3333865.pax2 and 8.jpg|Early expression of Pax2 and Pax8 compared
Image: otic placode embryo.jpg|Otic placode of an embryo
Image: neural fate.jpg|Recent model related to sensory fate.
Image: otic vesicle.jpg|Zebrafish otic vesicle
Image: z3333865.gene expression.jpeg|Representative expression patterns of genes controlling cochlear and vestibular specification.
Image: semi-circular canals.jpg|Wild-type semi-circular canal structure of zebrafish
Image: cochlea stereocilia bundle.jpg|Stereocilia bundles in the normal cochlea
Image: Mutation on GJB2 gene.jpg|Mutation on GJB2 gene
Image: Dominant_diagram.jpg|Dominant Inheritance
Image: Autosomal_Recessive_Inheritance_Diagram.jpg|Autosomal Recessive inheritance
Image: X_Linked_Recessive_Diagram.jpg|X-linked Recessive inheritance
Image: Basal Cochlear Outer Hair Cells.jpg| Scanning electron microscopy, showing hair cells of the basal and middle cochlea
Image: Pendred_Syndrome_Showing_Mondini_Defects.jpg|Pendred Syndrome
Image: MRI_of_Goldenhar_Syndrome.jpg|Goldenhar Syndrome
Image: Bilateral_Stenosis_of_Internal_Auditory_canal.jpg|Bilateral Stenosis of Internal Auditory Canal
Image: Enlarged_Vestibular_aqueduct.jpg|Enlarged Vestibular Aqueduct
Image: Microtia_boy_surgery.jpg|Microtia
Image: Infant hearing test.jpg|Testing the hearing of an infant - Auditory Brainstem Response test
Image: Hearing aids.JPG| Behind-the-ear (BTE), in-the-ear (ITE), in-the-canal (ITC), and completely-in-canal (CIC) hearing aids
Image: Cochlear_Implant.jpg|Cochlear Implant
Image: Atoh1 model.png|Atoh1-cre is expressed in hair cells and causes transient limited expression of Atoh1 in CKO ears
Image: Atoh1 hair cell loss.png|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.
Image: Aquaporins.png | Aquaporins 1, 4, and 5 in the inner ear (A-C) and middle ear (D-G) – staining by AQP. H: KCNJ10 also stained the middle ear epithelium. Negative controls are displayed as inset pictures

</gallery>

--[[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

2012-10-04T22:59:39Z

Z3292017: /* Cochlea Ear Implant */

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

==Introduction==

CAN YOU HEAR ME! – Hearing is one of the most important senses 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 and is inherent for both hunting and surviving. The sound energy produced has to be converted into an electrical signal for us to process this in our brain. For successful transmission the correct development of the ear is of utmost important. Not only the formation of the structures but also their correct assembly is imperative to normal ear functioning. In this project we will discuss the development of the human ear from implantation to birth by shining light on the differentiation of cells and signalling mechanisms that lead to normal development. We will then talk about some abnormal processes and mutations which lead to various structural and functional diseases. Technologies to detect and overcome these abnormalities will also be considered.

==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 was 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'''|| The labyrinth of the ear is discovered. <ref name="PMID11314703"><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 name="PMID11314703"/> [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. <ref name="PMID16269359"><pubmed>16269359</pubmed></ref> <ref><pubmed>11237469</pubmed></ref>

[[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. <ref name="PMID16269359"/>

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. <ref name="PMID16269359"/> <ref><pubmed>21774850</pubmed></ref>

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==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px]]

The development of the outer and middle ear is attributed to the pharyngeal arches one and two. All the germ layer namely endoderm, mesoderm and ectoderm contribute to its formation. <ref><pubmed>8287791</pubmed></ref> The entire inner ear, as well as the neurons which innervate the sensory organ, are derived from the otic placode. <ref name="PMID17891709"><pubmed>17891709</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 and middle ear structures. 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. <ref><pubmed>11698185</pubmed></ref> 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.<ref name="PMID17891709"/> This will form an otic vesicle (otocyst) and further develop into the structures of the inner ear.

We will consider the outer, middle and inner ear separately.

===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 increases 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, then following with the others 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 splits in week 15, 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 name="PMID10976045"><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.

[[File: middle ear ossicles.png|left|thumb|250px|A view from inside the tympanic cavity of ''Lagenorhynchus obliquidens'' (Pacific White-sided Dolphin)]]

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 name="PMID10976045"/> <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.<ref name="PMID17891709"/>It is generally visible after gastrulation, once the first 5 to 10 pairs of somites have formed - week 3 of human embryonic development. Invagination occurs next, which creates the otocyst. Patterning occurs and as a result, we can see the start of formation of the cochlea during week 5. The otocyst 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"/> Chondrification and ossification of the otic capsule takes places from week 9 and week 11 respectively.[[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>
[[File:z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared]]

'''2''' ''Pre-otic field''

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"/>
[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]

'''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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|210px| Zebrafish otic vesicle]]

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'''
[[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''
[[File:semi-circular canals.jpg|thumb|300px| Wild-type semi-circular canal structure of zebrafish]]
It is also crucial for normal development of inner ear structures that Hedgehog signalling is repressed. <ref><pubmed>20223756</pubmed></ref>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them. <ref><pubmed>22778034</pubmed></ref>

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.<ref><pubmed>12530227</pubmed></ref> It exits through the internal acoustic meatus (IAM) to conduct signals to the brain for processing.

====Summary inner ear====

{| cellpadding=5 style="border:2px solid #00FF00"
|- bgcolor= #CCFF00
|'''SUMMARY OF THE INNER EAR DEVELOPMENT'''
|- 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 the 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.

* The semi-circular canals and the cochlea form as elongations of the otocyst, from the superior and inferior aspect respectively. The vestibulocochlear nerve is formed from cells lining the otocyst as well as cranial neural crest cells.
|}

==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 name="PMID10980526"><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 name="PMID10980526"/>.
* 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>PMC3335728</pubmed></ref>.

|}

'''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
* Usher Syndrome predominantly affects the outer hair cells in the cochlear. Cochlear implants have given great improvements in both hearing and quality of life in these patients.
* 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 classic structural deformity is Mondini dysplasia of the cochlear whereby the cochlear is not complete having less than the required two and a half turns <ref><pubmed>3776519</pubmed></ref>.
* 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>.

||
[[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. It was also identified that 15 of the 23,000 pregnancies vertical transmission of the child contracting congenital toxoplasmosis <ref name="PMID3041362"><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* Detection of toxoplasmosis is achived through amniocentesis and subsequently using PCR to determine a positive result from DNA amplification <ref name="PMID3041362"/>.
* 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>. However inconclusive and inconsistent treatment investigations suggested to be caused by limited randomised controlled trials <ref><pubmed> 9988811 </pubmed></ref>.

|- bgcolor="#AAF0D1"
|''Rubella'' ||
* In 1979 an article provided evidence of the direct link between rubella and sensorineural deafness finding 24% of the hearing impaired children tested had the rubella antibody <ref><pubmed>84910</pubmed></ref>.
* Fetal infection risk will differ throughout the duration of the pregnancy. Week 1 to 10 has 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. There is a dramatic decrease in the second and third trimester (due to maternal antibodies and fetal cell mediated immune responses) however it goes back to 100% in the last month of pregnancy.
*Rubella infects the placenta via maternal viraemia which leads to necrotic areas in the chorionic villae epithelium <ref><pubmed>5949097</pubmed></ref>. It is thought that the rubella virus is passed through the fetal circulation via endothelial cell emboli. <ref><pubmed>2817948</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* It is an entirely preventable disease through the Rubella vaccine, being almost completely eliminated in western countries.

|- 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.
* Two 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 <ref><pubmed>3067168</pubmed></ref>
# 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''Drugs'''

{| cellpadding=5 style="border:1px solid #FF0090"
|- bgcolor="#FF55A3"
|'''Drug'''||'''Description'''
|- bgcolor="#FFF0F5"
|''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 <ref name="PMID9161611"><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 greater amount of apoptosis during the inner ear development and thus decreased growth of neurons and myelin and subsequently the synapses. Intermittent conductive hearing loss is thought to be due to poorly formed eustachian tube <ref><pubmed>12795509</pubmed></ref>.
* The central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing <ref name="PMID9161611"/>.

|- bgcolor="#FFA6C9"
|''Isotretinoin'' ||
* Isotretinoin is a treatment option for patients with severe cystic acne.
* It is teratogenic and its associated congenital malformations include: Lack of ears and malformations of the inner, middle and outer ears, along with mental retardations, facial malformations and heart and limb defects. <ref><pubmed>PMC1859978</pubmed></ref>.
* This is thought to be due to the ear not reaching full development such as the Mondini malformation.
* The most severe inner ear abnormalities occur when the mother was taking isotretinoin during the gastrulation stage, with the abnormalities indicating that the development was interrupted. It is thought that this is due to the disruption of the neural crest cell population. <ref><pubmed>1440418</pubmed></ref>

|- bgcolor="#FFF0F5"
|''Thalidomide'' ||
* Thalidomide was a drug used to ease morning sickness symptoms in the 1950's and 1960's until it was found to be teratogenic.
* Known for its limb reduction abnormalities, it also contributes to outer and inner ear malformations and heart and eye defects.
* Critical time periods for exposure to Thalidomide for outer ear malformations was days 20-24 post fertilisation and inner ear from day 24-34.
* Thalidomide is thought to increase the oxygen radical formation which generates oxidative stress along with inhibiting angiogenesis <ref><pubmed>21507989</pubmed></ref>.
|}

===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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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 - Auditory Brainstem Response test]]

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===
[[File:Hearing_aids.JPG|thumb|200 px|right| 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 amplification 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 amplification 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 amplifier. The amplifier sends the impulses though the speaker into the ear as an increased sound.
<ref>National Institute of Health, '''Hearing Aid Basics''', http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx, Access date 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>6028666</pubmed></ref>

[[File:Cochlear_Implant.jpg|thumb|x250px|Cochlear Implant]]

==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

*'''Nonsyndromic deafness''': Hearing impairment not affiliated with other signs or symptoms

*'''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

*'''Syndromic deafness''': Hearing impairment occurring with additional abnormalities in the body

*'''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

== References ==
<references/>

==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]

{{External Links}}

==Image Gallery==

<gallery>

Image: Z3333865.Ruby.jpeg|EARS
Image: Anatomy_of_the_Ear.JPG|Anatomy of the ear
Image: Histology_of_Inner_Ear.png|Histology of Inner Ear
Image: Pharyngeal_arch_one_and_two_in_mice.png|Pharyngeal arches one and two in mice embryo
Image: Devt_of_external_ear.JPG|The image depicts the development of the pinna through the fetal development stages
Image: middle ear ossicles.png|A view from inside the tympanic cavity of ''Lagenorhynchus obliquidens'' (Pacific White-sided Dolphin)
Image: normal cochlea.png |Wild-type inner ear showing normal morphology
Image: z3333865.pax2 and 8.jpg|Early expression of Pax2 and Pax8 compared
Image: otic placode embryo.jpg|Otic placode of an embryo
Image: neural fate.jpg|Recent model related to sensory fate.
Image: otic vesicle.jpg|Zebrafish otic vesicle
Image: z3333865.gene expression.jpeg|Representative expression patterns of genes controlling cochlear and vestibular specification.
Image: semi-circular canals.jpg|Wild-type semi-circular canal structure of zebrafish
Image: cochlea stereocilia bundle.jpg|Stereocilia bundles in the normal cochlea
Image: Mutation on GJB2 gene.jpg|Mutation on GJB2 gene
Image: Dominant_diagram.jpg|Dominant Inheritance
Image: Autosomal_Recessive_Inheritance_Diagram.jpg|Autosomal Recessive inheritance
Image: X_Linked_Recessive_Diagram.jpg|X-linked Recessive inheritance
Image: Basal Cochlear Outer Hair Cells.jpg| Scanning electron microscopy, showing hair cells of the basal and middle cochlea
Image: Pendred_Syndrome_Showing_Mondini_Defects.jpg|Pendred Syndrome
Image: MRI_of_Goldenhar_Syndrome.jpg|Goldenhar Syndrome
Image: Bilateral_Stenosis_of_Internal_Auditory_canal.jpg|Bilateral Stenosis of Internal Auditory Canal
Image: Enlarged_Vestibular_aqueduct.jpg|Enlarged Vestibular Aqueduct
Image: Microtia_boy_surgery.jpg|Microtia
Image: Infant hearing test.jpg|Testing the hearing of an infant - Auditory Brainstem Response test
Image: Hearing aids.JPG| Behind-the-ear (BTE), in-the-ear (ITE), in-the-canal (ITC), and completely-in-canal (CIC) hearing aids
Image: Cochlear_Implant.jpg|Cochlear Implant
Image: Atoh1 model.png|Atoh1-cre is expressed in hair cells and causes transient limited expression of Atoh1 in CKO ears
Image: Atoh1 hair cell loss.png|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.
Image: Aquaporins.png | Aquaporins 1, 4, and 5 in the inner ear (A-C) and middle ear (D-G) – staining by AQP. H: KCNJ10 also stained the middle ear epithelium. Negative controls are displayed as inset pictures

</gallery>

--[[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

2012-10-04T22:56:42Z

Z3292017: /* Cochlea Ear Implant */

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

==Introduction==

CAN YOU HEAR ME! – Hearing is one of the most important senses 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 and is inherent for both hunting and surviving. The sound energy produced has to be converted into an electrical signal for us to process this in our brain. For successful transmission the correct development of the ear is of utmost important. Not only the formation of the structures but also their correct assembly is imperative to normal ear functioning. In this project we will discuss the development of the human ear from implantation to birth by shining light on the differentiation of cells and signalling mechanisms that lead to normal development. We will then talk about some abnormal processes and mutations which lead to various structural and functional diseases. Technologies to detect and overcome these abnormalities will also be considered.

==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 was 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'''|| The labyrinth of the ear is discovered. <ref name="PMID11314703"><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 name="PMID11314703"/> [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. <ref name="PMID16269359"><pubmed>16269359</pubmed></ref> <ref><pubmed>11237469</pubmed></ref>

[[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. <ref name="PMID16269359"/>

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. <ref name="PMID16269359"/> <ref><pubmed>21774850</pubmed></ref>

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==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px]]

The development of the outer and middle ear is attributed to the pharyngeal arches one and two. All the germ layer namely endoderm, mesoderm and ectoderm contribute to its formation. <ref><pubmed>8287791</pubmed></ref> The entire inner ear, as well as the neurons which innervate the sensory organ, are derived from the otic placode. <ref name="PMID17891709"><pubmed>17891709</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 and middle ear structures. 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. <ref><pubmed>11698185</pubmed></ref> 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.<ref name="PMID17891709"/> This will form an otic vesicle (otocyst) and further develop into the structures of the inner ear.

We will consider the outer, middle and inner ear separately.

===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 increases 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, then following with the others 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 splits in week 15, 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 name="PMID10976045"><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.

[[File: middle ear ossicles.png|left|thumb|250px|A view from inside the tympanic cavity of ''Lagenorhynchus obliquidens'' (Pacific White-sided Dolphin)]]

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 name="PMID10976045"/> <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.<ref name="PMID17891709"/>It is generally visible after gastrulation, once the first 5 to 10 pairs of somites have formed - week 3 of human embryonic development. Invagination occurs next, which creates the otocyst. Patterning occurs and as a result, we can see the start of formation of the cochlea during week 5. The otocyst 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"/> Chondrification and ossification of the otic capsule takes places from week 9 and week 11 respectively.[[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>
[[File:z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared]]

'''2''' ''Pre-otic field''

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"/>
[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]

'''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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|210px| Zebrafish otic vesicle]]

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'''
[[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''
[[File:semi-circular canals.jpg|thumb|300px| Wild-type semi-circular canal structure of zebrafish]]
It is also crucial for normal development of inner ear structures that Hedgehog signalling is repressed. <ref><pubmed>20223756</pubmed></ref>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them. <ref><pubmed>22778034</pubmed></ref>

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.<ref><pubmed>12530227</pubmed></ref> It exits through the internal acoustic meatus (IAM) to conduct signals to the brain for processing.

====Summary inner ear====

{| cellpadding=5 style="border:2px solid #00FF00"
|- bgcolor= #CCFF00
|'''SUMMARY OF THE INNER EAR DEVELOPMENT'''
|- 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 the 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.

* The semi-circular canals and the cochlea form as elongations of the otocyst, from the superior and inferior aspect respectively. The vestibulocochlear nerve is formed from cells lining the otocyst as well as cranial neural crest cells.
|}

==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 name="PMID10980526"><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 name="PMID10980526"/>.
* 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>PMC3335728</pubmed></ref>.

|}

'''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
* Usher Syndrome predominantly affects the outer hair cells in the cochlear. Cochlear implants have given great improvements in both hearing and quality of life in these patients.
* 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 classic structural deformity is Mondini dysplasia of the cochlear whereby the cochlear is not complete having less than the required two and a half turns <ref><pubmed>3776519</pubmed></ref>.
* 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>.

||
[[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. It was also identified that 15 of the 23,000 pregnancies vertical transmission of the child contracting congenital toxoplasmosis <ref name="PMID3041362"><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* Detection of toxoplasmosis is achived through amniocentesis and subsequently using PCR to determine a positive result from DNA amplification <ref name="PMID3041362"/>.
* 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>. However inconclusive and inconsistent treatment investigations suggested to be caused by limited randomised controlled trials <ref><pubmed> 9988811 </pubmed></ref>.

|- bgcolor="#AAF0D1"
|''Rubella'' ||
* In 1979 an article provided evidence of the direct link between rubella and sensorineural deafness finding 24% of the hearing impaired children tested had the rubella antibody <ref><pubmed>84910</pubmed></ref>.
* Fetal infection risk will differ throughout the duration of the pregnancy. Week 1 to 10 has 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. There is a dramatic decrease in the second and third trimester (due to maternal antibodies and fetal cell mediated immune responses) however it goes back to 100% in the last month of pregnancy.
*Rubella infects the placenta via maternal viraemia which leads to necrotic areas in the chorionic villae epithelium <ref><pubmed>5949097</pubmed></ref>. It is thought that the rubella virus is passed through the fetal circulation via endothelial cell emboli. <ref><pubmed>2817948</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* It is an entirely preventable disease through the Rubella vaccine, being almost completely eliminated in western countries.

|- 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.
* Two 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 <ref><pubmed>3067168</pubmed></ref>
# 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''Drugs'''

{| cellpadding=5 style="border:1px solid #FF0090"
|- bgcolor="#FF55A3"
|'''Drug'''||'''Description'''
|- bgcolor="#FFF0F5"
|''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 <ref name="PMID9161611"><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 greater amount of apoptosis during the inner ear development and thus decreased growth of neurons and myelin and subsequently the synapses. Intermittent conductive hearing loss is thought to be due to poorly formed eustachian tube <ref><pubmed>12795509</pubmed></ref>.
* The central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing <ref name="PMID9161611"/>.

|- bgcolor="#FFA6C9"
|''Isotretinoin'' ||
* Isotretinoin is a treatment option for patients with severe cystic acne.
* It is teratogenic and its associated congenital malformations include: Lack of ears and malformations of the inner, middle and outer ears, along with mental retardations, facial malformations and heart and limb defects. <ref><pubmed>PMC1859978</pubmed></ref>.
* This is thought to be due to the ear not reaching full development such as the Mondini malformation.
* The most severe inner ear abnormalities occur when the mother was taking isotretinoin during the gastrulation stage, with the abnormalities indicating that the development was interrupted. It is thought that this is due to the disruption of the neural crest cell population. <ref><pubmed>1440418</pubmed></ref>

|- bgcolor="#FFF0F5"
|''Thalidomide'' ||
* Thalidomide was a drug used to ease morning sickness symptoms in the 1950's and 1960's until it was found to be teratogenic.
* Known for its limb reduction abnormalities, it also contributes to outer and inner ear malformations and heart and eye defects.
* Critical time periods for exposure to Thalidomide for outer ear malformations was days 20-24 post fertilisation and inner ear from day 24-34.
* Thalidomide is thought to increase the oxygen radical formation which generates oxidative stress along with inhibiting angiogenesis <ref><pubmed>21507989</pubmed></ref>.
|}

===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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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 - Auditory Brainstem Response test]]

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===
[[File:Hearing_aids.JPG|thumb|200 px|right| 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 amplification 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 amplification 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 amplifier. The amplifier sends the impulses though the speaker into the ear as an increased sound.
<ref>National Institute of Health, '''Hearing Aid Basics''', http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx, Access date 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>6028666</pubmed></ref>

[[File:Cochlear_Implant.jpg|x250px|Cochlear Implant]]

==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

*'''Nonsyndromic deafness''': Hearing impairment not affiliated with other signs or symptoms

*'''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

*'''Syndromic deafness''': Hearing impairment occurring with additional abnormalities in the body

*'''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

== References ==
<references/>

==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]

{{External Links}}

==Image Gallery==

<gallery>

Image: Z3333865.Ruby.jpeg|EARS
Image: Anatomy_of_the_Ear.JPG|Anatomy of the ear
Image: Histology_of_Inner_Ear.png|Histology of Inner Ear
Image: Pharyngeal_arch_one_and_two_in_mice.png|Pharyngeal arches one and two in mice embryo
Image: Devt_of_external_ear.JPG|The image depicts the development of the pinna through the fetal development stages
Image: middle ear ossicles.png|A view from inside the tympanic cavity of ''Lagenorhynchus obliquidens'' (Pacific White-sided Dolphin)
Image: normal cochlea.png |Wild-type inner ear showing normal morphology
Image: z3333865.pax2 and 8.jpg|Early expression of Pax2 and Pax8 compared
Image: otic placode embryo.jpg|Otic placode of an embryo
Image: neural fate.jpg|Recent model related to sensory fate.
Image: otic vesicle.jpg|Zebrafish otic vesicle
Image: z3333865.gene expression.jpeg|Representative expression patterns of genes controlling cochlear and vestibular specification.
Image: semi-circular canals.jpg|Wild-type semi-circular canal structure of zebrafish
Image: cochlea stereocilia bundle.jpg|Stereocilia bundles in the normal cochlea
Image: Mutation on GJB2 gene.jpg|Mutation on GJB2 gene
Image: Dominant_diagram.jpg|Dominant Inheritance
Image: Autosomal_Recessive_Inheritance_Diagram.jpg|Autosomal Recessive inheritance
Image: X_Linked_Recessive_Diagram.jpg|X-linked Recessive inheritance
Image: Basal Cochlear Outer Hair Cells.jpg| Scanning electron microscopy, showing hair cells of the basal and middle cochlea
Image: Pendred_Syndrome_Showing_Mondini_Defects.jpg|Pendred Syndrome
Image: MRI_of_Goldenhar_Syndrome.jpg|Goldenhar Syndrome
Image: Bilateral_Stenosis_of_Internal_Auditory_canal.jpg|Bilateral Stenosis of Internal Auditory Canal
Image: Enlarged_Vestibular_aqueduct.jpg|Enlarged Vestibular Aqueduct
Image: Microtia_boy_surgery.jpg|Microtia
Image: Infant hearing test.jpg|Testing the hearing of an infant - Auditory Brainstem Response test
Image: Hearing aids.JPG| Behind-the-ear (BTE), in-the-ear (ITE), in-the-canal (ITC), and completely-in-canal (CIC) hearing aids
Image: Cochlear_Implant.jpg|Cochlear Implant
Image: Atoh1 model.png|Atoh1-cre is expressed in hair cells and causes transient limited expression of Atoh1 in CKO ears
Image: Atoh1 hair cell loss.png|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.
Image: Aquaporins.png | Aquaporins 1, 4, and 5 in the inner ear (A-C) and middle ear (D-G) – staining by AQP. H: KCNJ10 also stained the middle ear epithelium. Negative controls are displayed as inset pictures

</gallery>

--[[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

2012-10-04T22:55:09Z

Z3292017: /* Cochlea Ear Implant */

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

==Introduction==

CAN YOU HEAR ME! – Hearing is one of the most important senses 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 and is inherent for both hunting and surviving. The sound energy produced has to be converted into an electrical signal for us to process this in our brain. For successful transmission the correct development of the ear is of utmost important. Not only the formation of the structures but also their correct assembly is imperative to normal ear functioning. In this project we will discuss the development of the human ear from implantation to birth by shining light on the differentiation of cells and signalling mechanisms that lead to normal development. We will then talk about some abnormal processes and mutations which lead to various structural and functional diseases. Technologies to detect and overcome these abnormalities will also be considered.

==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 was 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'''|| The labyrinth of the ear is discovered. <ref name="PMID11314703"><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 name="PMID11314703"/> [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. <ref name="PMID16269359"><pubmed>16269359</pubmed></ref> <ref><pubmed>11237469</pubmed></ref>

[[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. <ref name="PMID16269359"/>

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. <ref name="PMID16269359"/> <ref><pubmed>21774850</pubmed></ref>

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==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px]]

The development of the outer and middle ear is attributed to the pharyngeal arches one and two. All the germ layer namely endoderm, mesoderm and ectoderm contribute to its formation. <ref><pubmed>8287791</pubmed></ref> The entire inner ear, as well as the neurons which innervate the sensory organ, are derived from the otic placode. <ref name="PMID17891709"><pubmed>17891709</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 and middle ear structures. 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. <ref><pubmed>11698185</pubmed></ref> 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.<ref name="PMID17891709"/> This will form an otic vesicle (otocyst) and further develop into the structures of the inner ear.

We will consider the outer, middle and inner ear separately.

===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 increases 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, then following with the others 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 splits in week 15, 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 name="PMID10976045"><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.

[[File: middle ear ossicles.png|left|thumb|250px|A view from inside the tympanic cavity of ''Lagenorhynchus obliquidens'' (Pacific White-sided Dolphin)]]

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 name="PMID10976045"/> <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.<ref name="PMID17891709"/>It is generally visible after gastrulation, once the first 5 to 10 pairs of somites have formed - week 3 of human embryonic development. Invagination occurs next, which creates the otocyst. Patterning occurs and as a result, we can see the start of formation of the cochlea during week 5. The otocyst 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"/> Chondrification and ossification of the otic capsule takes places from week 9 and week 11 respectively.[[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>
[[File:z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared]]

'''2''' ''Pre-otic field''

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"/>
[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]

'''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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|210px| Zebrafish otic vesicle]]

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'''
[[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''
[[File:semi-circular canals.jpg|thumb|300px| Wild-type semi-circular canal structure of zebrafish]]
It is also crucial for normal development of inner ear structures that Hedgehog signalling is repressed. <ref><pubmed>20223756</pubmed></ref>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them. <ref><pubmed>22778034</pubmed></ref>

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.<ref><pubmed>12530227</pubmed></ref> It exits through the internal acoustic meatus (IAM) to conduct signals to the brain for processing.

====Summary inner ear====

{| cellpadding=5 style="border:2px solid #00FF00"
|- bgcolor= #CCFF00
|'''SUMMARY OF THE INNER EAR DEVELOPMENT'''
|- 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 the 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.

* The semi-circular canals and the cochlea form as elongations of the otocyst, from the superior and inferior aspect respectively. The vestibulocochlear nerve is formed from cells lining the otocyst as well as cranial neural crest cells.
|}

==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 name="PMID10980526"><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 name="PMID10980526"/>.
* 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>PMC3335728</pubmed></ref>.

|}

'''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
* Usher Syndrome predominantly affects the outer hair cells in the cochlear. Cochlear implants have given great improvements in both hearing and quality of life in these patients.
* 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 classic structural deformity is Mondini dysplasia of the cochlear whereby the cochlear is not complete having less than the required two and a half turns <ref><pubmed>3776519</pubmed></ref>.
* 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>.

||
[[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. It was also identified that 15 of the 23,000 pregnancies vertical transmission of the child contracting congenital toxoplasmosis <ref name="PMID3041362"><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* Detection of toxoplasmosis is achived through amniocentesis and subsequently using PCR to determine a positive result from DNA amplification <ref name="PMID3041362"/>.
* 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>. However inconclusive and inconsistent treatment investigations suggested to be caused by limited randomised controlled trials <ref><pubmed> 9988811 </pubmed></ref>.

|- bgcolor="#AAF0D1"
|''Rubella'' ||
* In 1979 an article provided evidence of the direct link between rubella and sensorineural deafness finding 24% of the hearing impaired children tested had the rubella antibody <ref><pubmed>84910</pubmed></ref>.
* Fetal infection risk will differ throughout the duration of the pregnancy. Week 1 to 10 has 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. There is a dramatic decrease in the second and third trimester (due to maternal antibodies and fetal cell mediated immune responses) however it goes back to 100% in the last month of pregnancy.
*Rubella infects the placenta via maternal viraemia which leads to necrotic areas in the chorionic villae epithelium <ref><pubmed>5949097</pubmed></ref>. It is thought that the rubella virus is passed through the fetal circulation via endothelial cell emboli. <ref><pubmed>2817948</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* It is an entirely preventable disease through the Rubella vaccine, being almost completely eliminated in western countries.

|- 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.
* Two 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 <ref><pubmed>3067168</pubmed></ref>
# 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''Drugs'''

{| cellpadding=5 style="border:1px solid #FF0090"
|- bgcolor="#FF55A3"
|'''Drug'''||'''Description'''
|- bgcolor="#FFF0F5"
|''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 <ref name="PMID9161611"><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 greater amount of apoptosis during the inner ear development and thus decreased growth of neurons and myelin and subsequently the synapses. Intermittent conductive hearing loss is thought to be due to poorly formed eustachian tube <ref><pubmed>12795509</pubmed></ref>.
* The central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing <ref name="PMID9161611"/>.

|- bgcolor="#FFA6C9"
|''Isotretinoin'' ||
* Isotretinoin is a treatment option for patients with severe cystic acne.
* It is teratogenic and its associated congenital malformations include: Lack of ears and malformations of the inner, middle and outer ears, along with mental retardations, facial malformations and heart and limb defects. <ref><pubmed>PMC1859978</pubmed></ref>.
* This is thought to be due to the ear not reaching full development such as the Mondini malformation.
* The most severe inner ear abnormalities occur when the mother was taking isotretinoin during the gastrulation stage, with the abnormalities indicating that the development was interrupted. It is thought that this is due to the disruption of the neural crest cell population. <ref><pubmed>1440418</pubmed></ref>

|- bgcolor="#FFF0F5"
|''Thalidomide'' ||
* Thalidomide was a drug used to ease morning sickness symptoms in the 1950's and 1960's until it was found to be teratogenic.
* Known for its limb reduction abnormalities, it also contributes to outer and inner ear malformations and heart and eye defects.
* Critical time periods for exposure to Thalidomide for outer ear malformations was days 20-24 post fertilisation and inner ear from day 24-34.
* Thalidomide is thought to increase the oxygen radical formation which generates oxidative stress along with inhibiting angiogenesis <ref><pubmed>21507989</pubmed></ref>.
|}

===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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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 - Auditory Brainstem Response test]]

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===
[[File:Hearing_aids.JPG|thumb|200 px|right| 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 amplification 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 amplification 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 amplifier. The amplifier sends the impulses though the speaker into the ear as an increased sound.
<ref>National Institute of Health, '''Hearing Aid Basics''', http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx, Access date 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>6028666</pubmed></ref>

[[File:Cochlear_Implant.jpg|thumb|x250px|left|Cochlear Implant]]

==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

*'''Nonsyndromic deafness''': Hearing impairment not affiliated with other signs or symptoms

*'''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

*'''Syndromic deafness''': Hearing impairment occurring with additional abnormalities in the body

*'''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

== References ==
<references/>

==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]

{{External Links}}

==Image Gallery==

<gallery>

Image: Z3333865.Ruby.jpeg|EARS
Image: Anatomy_of_the_Ear.JPG|Anatomy of the ear
Image: Histology_of_Inner_Ear.png|Histology of Inner Ear
Image: Pharyngeal_arch_one_and_two_in_mice.png|Pharyngeal arches one and two in mice embryo
Image: Devt_of_external_ear.JPG|The image depicts the development of the pinna through the fetal development stages
Image: middle ear ossicles.png|A view from inside the tympanic cavity of ''Lagenorhynchus obliquidens'' (Pacific White-sided Dolphin)
Image: normal cochlea.png |Wild-type inner ear showing normal morphology
Image: z3333865.pax2 and 8.jpg|Early expression of Pax2 and Pax8 compared
Image: otic placode embryo.jpg|Otic placode of an embryo
Image: neural fate.jpg|Recent model related to sensory fate.
Image: otic vesicle.jpg|Zebrafish otic vesicle
Image: z3333865.gene expression.jpeg|Representative expression patterns of genes controlling cochlear and vestibular specification.
Image: semi-circular canals.jpg|Wild-type semi-circular canal structure of zebrafish
Image: cochlea stereocilia bundle.jpg|Stereocilia bundles in the normal cochlea
Image: Mutation on GJB2 gene.jpg|Mutation on GJB2 gene
Image: Dominant_diagram.jpg|Dominant Inheritance
Image: Autosomal_Recessive_Inheritance_Diagram.jpg|Autosomal Recessive inheritance
Image: X_Linked_Recessive_Diagram.jpg|X-linked Recessive inheritance
Image: Basal Cochlear Outer Hair Cells.jpg| Scanning electron microscopy, showing hair cells of the basal and middle cochlea
Image: Pendred_Syndrome_Showing_Mondini_Defects.jpg|Pendred Syndrome
Image: MRI_of_Goldenhar_Syndrome.jpg|Goldenhar Syndrome
Image: Bilateral_Stenosis_of_Internal_Auditory_canal.jpg|Bilateral Stenosis of Internal Auditory Canal
Image: Enlarged_Vestibular_aqueduct.jpg|Enlarged Vestibular Aqueduct
Image: Microtia_boy_surgery.jpg|Microtia
Image: Infant hearing test.jpg|Testing the hearing of an infant - Auditory Brainstem Response test
Image: Hearing aids.JPG| Behind-the-ear (BTE), in-the-ear (ITE), in-the-canal (ITC), and completely-in-canal (CIC) hearing aids
Image: Cochlear_Implant.jpg|Cochlear Implant
Image: Atoh1 model.png|Atoh1-cre is expressed in hair cells and causes transient limited expression of Atoh1 in CKO ears
Image: Atoh1 hair cell loss.png|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.
Image: Aquaporins.png | Aquaporins 1, 4, and 5 in the inner ear (A-C) and middle ear (D-G) – staining by AQP. H: KCNJ10 also stained the middle ear epithelium. Negative controls are displayed as inset pictures

</gallery>

--[[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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{{2012Projects}}

File:Cochlear Implant.jpg

2012-10-04T22:51:19Z

Z3292017:

Description: Illustration of the cochlear implant.

Reference: http://www.nidcd.nih.gov/health/hearing/pages/coch.aspx

Copyright: National Institute on Deafness and Other Communication Disorders at the National Institutes of Health. Unless otherwise stated, the information on this site is not copyrighted and is in the public domain. It is free for the public to use, copy, and distribute. You may encounter documents that were sponsored along with private companies or other organizations. Those documents will have statements that protect them under U.S. and foreign copyright laws.

{{Template:Student Image}}

File:X Linked Recessive Diagram.jpg

2012-10-04T22:45:17Z

Z3292017:

Description: A simplistic summary of X linked recessive inheritance

Copyright: I (z3292017) grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode."

File:Mutation on GJB2 gene.jpg

2012-10-04T22:44:01Z

Z3292017:

Description: The GJB2 gene (yellow arrow) is located on the long arm of chromosome 13 between positions 11 and 12.
More precisely, the GJB2 gene is located from base pair 20,761,601 to base pair 20,767,113 on chromosome 13.

Reference: 2012 http://ghr.nlm.nih.gov/gene/GJB2#conditions

Copyright: Government information at NLM Web sites is in the public domain. Public domain information may be freely distributed and copied, but it is requested that in any subsequent use the National Library of Medicine (NLM) be given appropriate acknowledgement. When using NLM Web sites, you may encounter documents, illustrations, photographs, or other information resources contributed or licensed by private individuals, companies, or organizations that may be protected by U.S. and foreign copyright laws. Transmission or reproduction of protected items beyond that allowed by fair use as defined in the copyright laws requires the written permission of the copyright owners. Specific NLM Web sites containing protected information provide additional notification of conditions associated with its use.

{{Template:Student Image}}

File:Dominant diagram.jpg

2012-10-04T22:38:27Z

Z3292017:

Description: A simplistic summary of the transmission of autosomal genes through a family tree.

Copyright: I (z3292017) grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode."

File:Autosomal Recessive Inheritance Diagram.jpg

2012-10-04T22:38:08Z

Z3292017:

Description: A simplistic summary of the autosomal recessive inheritance transmission

Copyright: I (z3292017) grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode."

File:Dominant diagram.jpg

2012-10-04T22:37:05Z

Z3292017:

Description: A simplistic summary of the transmission of autosomal genes through a family tree.

I (z3292017) grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode."

Talk:2012 Group Project 6

2012-10-04T03:41:35Z

Z3292017: /* Our Thoughts - put new comment at the top please */

{{2012GroupDiscussion}}

This is a recent review on hearing. http://jcb.rupress.org/content/190/1/9.full JCB content allows reuse.

=Student evaluations=

I liked the tone of the introduction, it was light hearted and enjoyable to read, especially the image of the dog in the beginning which I thought was great. It also instructed the reader about the content of the page, thereby having a good balance between being engaging and informative.

The development section is extremely detailed, which is good in terms of showing a breadth of research and understanding however this needs to be offset with a greater deal of visual information. The subsections detailing the middle and outer ear are in need of some images showing the pharyngeal arches and their morphological changes from week to week. It would also be nice to see either some hand drawn images or computer drawn diagrams included somewhere in the page just for some variation. Towards the end of the page in the Abnormal hearing and the technological sections it tends to become very text heavy and need some image content. For example a photo of a cochlear implant would be useful.

There is some variation in the referencing style in Technology section with references appearing at the end of the section. It would be better to incorporate these references into the text as endnotes as they appear in the other sections of the project. Furthermore some of the tables are incomplete and require the addition of images. The image column in the structural malformations of the ear is empty. I’m not sure if there was a formatting problem or otherwise, though this need to be rectified.

Overall the page is very well written with an appropriate style aimed at students of the same level or higher. The glossary is extensive as is the reference list, showing an obvious depth of research.

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'''Please use this space to post your Group 6 student evaluation'''
Very clever start to the page. Introductory picture and statement draws reader in. Succinct but depth of information is really good. Somewhat overwhelming, but still very good. Break up in the information a little more.

The use of tables is really good and the coloured textbox was eye-catching and informative, similar to a textbook summary and great for wiki.

Distribution of abnormalities between environmental and genetic was also very good but further subheading for each syndrome would be better for quick access to desired information.

The development of the ear section is very well researched and informative but need pictures. I see that you havn’t gotten to really uploading lots of pictures yet but it’s really quite essential for you to do this esp. for this section as it’s the main focus. A few had drawn ones would be sufficient.

The extensive references are also impressinve.

Summary: break up sections more and more hand drawn images.

Good luck with the rest ☺

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This whole page I think is done really well. There is a balance between texts and images, it goes through the developmental process in detail, all information is relevant, there is an extensive use of resources and a pretty good glossary as well.

The image right at the beginning of the dog is very smart as it draws attention to the whole page. Also the “Can you hear me” at the beginning gives the expectation that the page as a whole is going to be really good so I thought that was very effective.

More information can be added to the current research section, and also you should try referencing throughout the entire page could be done a little better.

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Really funny image of the large eared dog is a great way to capture reader attention. It’s nice to see the importance of hearing in so many aspects of our lives. Finishing the introduction with an outline of the project is very appropriate because it sets up a framework of what you are going to talk about Overall, the introduction was very well written. The language is beautiful. However, there is a typo in ‘energy produced has be converted’.

Information presented in the history table was succinct and brief. It would be good to include proper references (in text citations) for each entry. There seems to be a gap between 1898 and 1978. Have there been any discoveries in those 80 years? It just seems like a big leap to go from the first portable electric hearing aid to a cochlear implant without any advances in hearing aid technology in between those years.

Anatomy of the ear was very clear. The text related to the picture nicely. The image enables readers to see all parts of the ear in relation to each other. It would nice to put an enlarged image of the inner ear and organ of Corti. Some people might not know what a ‘utricle’ or ‘saccule’ looks like and on that image it may be too hard to see.

With the development section, it would be good to include some images related to the development of outer, middle and inner ear. For example, include an image of week 5 embryo and label where the pharyngeal arches are so people with no background in embryology can understand what parts of the embryo you are referring to. Some of terminology, such as ‘auricular enlargement’, ‘tragus’ and ‘helix’, is hard to understand. Relevant images would help.

It would be good to put in text citations after important sentences in the paragraphs of outer, inner and middle ear development. This is because a couple of paragraphs (e.g. the middle ear paragraph) had several citations at the end of the paragraph and we don’t know which sentence or fact corresponds to which citation.

In the ‘Otic placode’ section, it’s great to see the images well referenced and have the correct copyright. ‘Early expression of Pax2 and Pax8 compared’ and ‘The expression of Sox2 and Sox3 during development of the ear’ images were useful because they reflected the processes outlined in the text. Maybe simplify the signalling information on the FGFs because I found it hard to understand. Maybe give a summary of the roles of the major factors – a table, showing ‘factor...process it controls’, would be nice.

‘Recent model related to sensory fate’ image made a complex process simple – this is great to see. ‘Establishing polarity and formation of inner ear structures’ section was very well written. Maybe put this under the same section as the inner ear. I feel the 2 sections are related.

Abnormal hearing section was very detailed and extensive. It covered so many hearing abnormalities. It would be good to include available treatments for some of the diseases and give a summary table – ‘causes...disease...description of disease...prevalence...treatments’.
--[[User:Z3332863|Z3332863]] 14:34, 25 September 2012 (EST)

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"The humorous image at the beginning accompanied by the “CAN YOU HEAR ME” in the introduction was a very clever way of drawing the reader in and making your message loud and clear, with all pun intended. Great work! I like how you also clearly introduced what your page will discuss.

No issues with the history timeline – it is well set out and very clear and concise. The section of the Adult Anatomy is quite clear also, however you refer to histology in the title – perhaps include an image that shows the histology of a certain structure. In regards to the section on Development, it is very clear that a lot of work has gone into this. However, be aware that you must reference all your information to avoid being penalised or accused of plagiarism. Additionally, images would help your explanations – it is slightly word dense at the moment so perhaps arrange some of the content into dot points in order to engage your reader. The sections on the Otic Placode and Otocyst are great examples of webpage layout, with the dot points and a clear image which links to the content. I especially liked how a summary of the inner ear was included – this demonstrates an awareness of peer teaching and reiterates your key points. Excellent!

The section on abnormal hearing was a joy to read and was cleverly set out in tables – the information will be even more enhanced by the images I can see you have indicated you will add. I also liked how you divided the different congenital abnormalities into environmental and genetic. In order to enhance these sections, incorporate some dot points or a diagram showing how viruses/drugs can cross the placenta.

The “Technologies to Detect” would best be organised under subheadings – at present it is a little daunting to read in the paragraph-paragraph format which is a shame because the information is very interesting! Also, be aware of correct referencing formats which you can find on the tutorial page – your in text references should be numbers and the references should go at the end of the webpage. I liked the “Technologies to overcome the problems” – may I suggest including images or diagrams of these technologies?

It would be great to see more examples of Current Research. However, what you have presented thus far is great – you have clearly described the aims and findings of research.

Overall, good work – just make sure you are consistent with referencing and strike a balance between images and text."

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What drew me into reading this page, was the humerous image at the beginning together with the perfect introduction that encourages people to read on. The sub-headings, headings, figures and tables make it really simple for the reader to take in all the key points of the research area. I particularly like the inclusion of technologies to detect abnormalities. However, this great balance is not met in the development section where there is too much text and not enough images or diagrams to guide the thinking. I would suggest trying to simplify the information into key points by eliminating any information that would not necessarily contribute to a sound understanding of the topic. This could possibly be achieved further by having a separation or different sub-heading for the description of the development process and the description of the cellular structure.

What stands out the most about this page, is the amount of research you have put in to the genetics and molecular processes of development and abnormalities. Whilst it is very interesting and shows the amount of time you've put into having a clear understanding, at times it seems the naming of genes and their proteins do not contribute to a sound understanding but rather adds confusion. For example, your reference to FGF and Sox are important but you have further included the different types of FGF and Sox proteins without offering much of an explanation about what distinguishes them from eachother. Generalising in these cases (to just FGF not FGF1,2,3..) would not limit the extent to which a student may learn from your information but will avoid any confusion.

Another way you could further improve the page is with the inclusion of student-drawn images or learning aids to accompany the text. This way you can avoid the inclusion of unnecessary information on borrowed images, for example, the wild-type inner ear morphology image. The referencing system is consistent and well set-out on the page and the long list of references and interesting discoveries is impressive. Overall I would just encourage condensing the information into dot points that help simplify the reader’s understanding.

Good luck!

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Good use of image, it attracts my attention straight away and it is very relaxing to look at a funny image before reading the text. Introduction is precise and to point, clearly identifying the purpose of the project and gives a general overview of what the readers will see or learn from the project. The timeline for history is good, but maybe indicate what kind of history is it? The adult anatomy and histology section is good but the heading should be "adult ear anatomy and histology"? I like it how the ear is divided into outer ear, middle ear and inner ear and then it is further divided into components that are included in these 3 different parts of the ear. This makes the structure of the ear very easy to understand and we can locate the different structure of the ear much easily. The image used in this section is very good with clearly labelled structures, the image also contained all the important information and referenced correctly but you forgot to include the student image template.

The development section is well-researched and contain a lot of information. More images should be put in to balance out the heavy text load in the section but the information provided is very in-depth and precise. The developmental process is explained in simple terms but i noticed that there is an imbalance in terms of research and information between middle ear and the other two. Maybe more research should be done on the middle ear. The summary of the inner idea was a good idea because it clearly points out the main points that readers should know, should consider do something similar for both the outer and middle ear.

The abnormal hearing section is well-researched and interesting. It is very nice to know about the association between gene mutation and its influence on hearing development. Maybe some images should be put here to balance out the text a bit. The table of genetic syndrome is very nice, maybe you can consider putting the gene mutations into table as well. The environmental section is nice and well-researched but maybe images should be put here because right now it is pretty boring just going through all the text. And there are just some weird reference under each infections but i think this can be fixed soon. Structural malformation of the ear table is nice as well, clearly showing all the important information. It will look even better when all the images are put in.

Overall, i thought the project is really good. Contained a lot of useful information and a lot of research effort has been put in, all the information are related to the research topic. The tables work really well and the structure of the page is easy to follow. Referencing is generally good but maybe get rid of some of the random citations in sections. More images should be put in to balance out the heavy text but I thought it was a very well-researched project. Hope this helps :)

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Group Assessment Criteria:
# ''The key points relating to the topic that your group was allocated are clearly described.'' The introduction clearly outlines the key points of the project and the content is well described in the text.
# ''The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.'' The choice of content and headings shows a good depth of research and understanding of the topic area. The ‘Summary of the inner ear’ table was a good idea and ties in all the information nicely.
# ''Content is correctly cited and referenced.'' There are large paragraphs of texts that have no references. The images provided display the copyright notices and explanations.
# ''The wiki has an element of teaching at a peer level using the student’s own innovative diagrams, tables or figures and/or using interesting examples or explanations.'' The introduction is well written and catches the readers interest and attention. Most of the normal development section is easy to understand, however the abnormalities section is difficult to understand due to the scientific jargon. Some hand-drawn images and tables would be beneficial in order to reduce the large paragraphs of text.
# ''Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'' The amount of information provided is evidence of the significant research that went into this project, and the sections such as ‘Technologies to overcome the problems’ shows research that goes ‘beyond the formal teaching activities’.
# ''Relates the topics and content of the Wiki entry to learning aims of embryology.'' The topics and content are well related to the learning aims of embryology
# ''The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning.'' All the content is relevant to the key areas of the development of the eye and demonstrates an extensive amount of research into the topic.

Additional points:
* The amount of text is overwhelming. You should make better use of tables, figures and diagrams to breakup/replace the text.
* Adult anatomy and histology: no reference to histology. Would be beneficial to have a brief explanation of the functions of each structure.
* Overall impression: Very well researched topic and I'm sure the use of tables, pictures and diagrams will make it more appealing to read!

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The image of the dog at the top of the page, while amusing, is not helpful nor appropriate for the academic nature of this website. The rest of the page however, is quite good. The information is extensive, very extensive. What i particularly like is that you have included a large amount of information on the actual development of the sense. It is easy with this assignment to talk at length amount the gross anatomy/physiology of the sense, without really dealing with the embryology of it.

As with most of the other projects, there are some sections that would benefit from a diagram or image. I know this is hard, especially for a paragraph dedicated to "mutation of gjb2 gene", but the large bloc of text is really quite trying for the reader. I found myself losing interest quite quickly.

Reference list is well pull together with a large body of research giving weight to your summary/ideas. Another this of note is how well explained your images are. This provides valuable information in trying to understand some of the ideas presented.

This is some discontinuity between the sections regarding how your present and list your information. This is probably just a by product of teamwork that can be ironed out easily.

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The introductory image at the top of the page is very good but the "can you hear me' bit was overkill for me - maybe consider revising that. Also the small spelling mistake at the start of the introduction (should be senses not sense) is quite off-putting and should be fixed. Otherwise a good introduction.

The history timeline is very good and serves as another good introduction to the topic. Some external links are missing here though.

For development there is a lot of information in the outer ear section but not much in the middle and inner sections - it looks imbalanced and may be improved by adding to the other sections or perhaps splitting up the sections differently. Other than this the development section is very good with a lot of well researched information. The images are also good but don't forget to add the "student template". The inclusion of the summary box is a very good idea and is a good feature of the page.

The abnormal section is also very good and well researched. The subheadings are used effectively and the tables are a good addition. Adding images in the tables as well as the text will help to break up the text and promote interest.

The technology sections are an interesting addition however could be improved by referencing using the wiki system rather than standard in-text citations.

A good start has been made in the current research section however if possible add more current topics of research.

The glossary is very good and the references are extensive however don't forget to add to the external links.

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Firstly the use of humour in this page is brilliant! Makes for an interesting and engaging read. The use of photographs and figures are particularly useful to help understand the topic but don't forget that the student template notice needs to be added to each photograph/diagram that you include. The referencing is great and extensive, perhaps though it might be an idea to see what is going on with reference number 56. The general layout of the page is really attractive too with a good balance of images and text, tables and especially the colourful Summary box. The content seems to address the course aims and requirements.

The introductory paragraph is to the point, well written and engaging. Similarly the structure and content included in the historic section is detailed and easy to read due to the table layout. The section about the development of the inner is well written but is somewhat overwhelming to look at just because of the amount of text. Maybe this could be combated by separating it into a few more paragraphs. The inclusion of genetic information in this area is great. The information under the subheading "The Otic Placode" onwards is particularly well done.

I like how the section on abnormalities is set out. However one problem with the area is the NOTE just before the table of genetic syndromes, I don't understand its purpose. Similarly the link in Goldenhar Syndrome entry appears random in comparison to the remainder of the entries.
Perhaps some more images in the abnormality section would be beneficial in breaking up the text. The paragraph discussing Rubella has two sentences in brackets at the bottom. Not sure why they are there either. If possible make "Infections" and "Drugs" into subheadings. I assume that information is still forthcoming for the section on Isotretinoin.

"Technologies to detect" is a good entry but perhaps consider changing subheading title as it is a little vague and incomplete. Also with this section there are loose references which should be included in the reference list at the bottom of the page rather than in the middle of the text. The information on hearing technology is brief but to the point. Again with the section on current research it may be an idea to include subheadings rather than bullet points, just so it is more easily accessed from the contents box at the top of the page.
Hope this helped.

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The introduction gives a good overview of the project and serves its purpose well. In addition, the technology section is another thing that stands out in this page along with the glossary and extensive referencing. These sections don't need to be worked on, but rather concentrate on expanding the page and adding a few more subheadings including headings of "current treatment" and "infection".

Information is very easy to follow due to the right choice of subheadings, tables and graphs. A few more tables and images with labels would make the information even easier to understand. Sometimes the amount of information becomes overwhelming, therefore try to break up the amount of texts by adding diagrams in between. Student hand drawn diagrams would be an excellent tool to employ as they can go well with the information provided.

The division of information between inner/middle/outer ear makes the structure easy to follow. This is a very good idea and an example as to how to break up the rest of the information which is all crammed together.
The citation and referencing seems to be correct, however, there are a number of paragraphs without any references, this is something that needs to be looked into. However, the level referencing at the end is great.

Also, there does not seem to be enough links. A few external links will benefit the page and allow readers to interact a fraction more.
Overall the page is very informative, however, altering the outlay and including a few diagrams, labeled images and external links would make the information easier to apprehend.

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Overall this is a well written page and is thoroughly researched.
While your introduction is small it is to the point. It gives an overview of hearing, its importance and outlines what your page is going to discuss.

The adult anatomy and histology part is confusing, I assume the adjacent image is related to the section and that development is a separate section. If that is so maybe the ear image should be thumb nailed or made smaller so that development looks like its own part.

Some images for development would be a nice addition to the well-researched information. While the class understands what it means others searching this page will have no point of reference as to what pharyngeal arches are for example, this is only a minor problem though.

The format of your development section is slightly confusing. Maybe by adding a line under inner and outer ear it would define it as a section on the respective area of development. I do like the summary of inner ear development at the end.

Technologies to detect, could possibly be name detection technologies/techniques has in text citations, I don’t think that these are necessary for this type of assignment.
--[[User:Z3220343|Z3220343]] 21:34, 25 September 2012 (EST)

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Group 6-Hearing

-you had me at puppy

-good intro (a few typos) and history (I like your table)

-the start of adult anatomy and histology should have an opening sentence instead of just listing information. There is no histology?

-I'm guessing the heading for development is meant to be bigger instead of it appearing to be part of "adult anatomy and histology"? This section is very comprehensive!

-your "neural domain" drawing is a good way of explaining this concept

-the summary box is a great idea, but perhaps it should be entitled "Summary of inner ear development"

-I don't understand why this is present- "NOTE: DEFINITIONS OF SYNDROMIC AND NON SYNDROMIC HEARING LOSS". You have explained what non-syndromic hearing loss is in the 1 Mutation of GJB2 gene section, but as your note says, it might be good to have a brief section with these definitions

-your genetic and structural disease tables are nice but I feel that the formatting should be the same for all of the diseases, or you should explain why you've chosen to emphasise these abnormalities

-the PDF in the Toxoplasmosis section seems to have some good info, but should be formatted like the other references

-the references in the rubella, cytomegalovirus infection, drugs and technologies to detect sections need to be formatted properly. Some info in drugs section isn't referenced at all

-technologies to detect is not a very informative heading, you need to specify what you're detecting. The syntax in this section and "technologies to overcome the problems" is poor (including the headings)

-in text hyperlinks in current research section are good for making page more interactive

-you appear to have used a lot of great resources

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Hearing review:

This group successfully energies the audience with a funny picture, along with a great introduction and an interactive writing style from the first paragraph. This page needs to address the reoccurring text to image ratio, allowing the reader more explanation complementing the hard work of explaining concepts. The highlight of this text was the abnormal hearing section which I found to be very interesting along with sound presentation of ideas. The demise of this page is the lack of information in current research and being starved of visual stimuli.
Overall a good attempt to line up embryological teaching concepts, when these easily addressable points are responded to a commendable finish will be apparent.

--[[User:Z3330795|Z3330795]] 09:55, 26 September 2012 (EST)

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Introduction needs more details. It has no references, so you need to research more and write more details with references. It would be good if you add an image of the ear with its structural components labelled, and explain the function of the structures.
The history section is too short so far. It needs more details and more references. Also, it would be good if you add images to support it.

Adult Anatomy and Histology has a good image, but you need more text details and you need to explain the structures more properly. And although ‘histology’ is mentioned in the heading, there is no explanation of the histology of the ears in the section at all. You need to reference the explanations of the ear structures.

Development section has a lot of detailed information so far, but needs more references and more images to balance the text. There is too much text but not enough images. The images that are currently there needs more description in the image details.
Genetic syndromes has a column that is labelled ‘images’ but there are no images there. You need to add images there.
Abnormal hearing section is very detailed and well done so far. However there is too much writing and no images at all. You need to add more images to balance the text to make it easier to read.

You may need some more examples in “Technologies to overcome the problems” section and you need to add more reference to the information posted so far.

Current research section needs a lot more work. Please add more article summaries and images with description from the articles to support the text.

Glossary section is good so far, but perhaps add some more words.
The reference section is good so far and has correct formatting.

There are no external links listed as of yet. Please add some useful external links.

---

Hearing

The introduction is concise and straight to the point. It gave an overview of the webpage and clearly indentified the purpose. The use of humor is welcoming though I think that image of the dog is over the top. Due to the great choice of subheadings, the development part is very easy to follow. More images to accompany the text would make it easier to understand would help break up some of the text. The current research section feels lacking. Referencing need to improve as some paragraphs have none.

=Hearing=

Normal and Abnormal

http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Infant_hearing_test.jpg

==Discussion Topics==

===Introduction===
Not what hearing is but what we are going to talk about

Image for hearing <pubmed>20624897</pubmed>
===History===

Research Contribution

==== Bartolomeo Eustachi 1514–1574 ====
Proposed that the tympanic membrane was connected to the nasopharynx was in the book ''De Auditus Organis'' in 1563. This was focusing on the the middle ear. His knowledge had allowed him to rediscover the tube found many years before and describe it correctly. This tube, the eustachian tube was named after him, by Antonio Maria Valsava and was shown in his book ''De aure humana tractatus''. <ref name="/PMC1142106"/> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142106 De aure humana tractatus.]

==== Antonio Maria Valsava 1666-1723 ====
The pioneer in the anatomy of the ear, published his first book ''De aure humana tractatus'' in 1704 this was the first to show and clearly describe the ear. He had been able to describe the anatomy and physiology of the ear by dissecting over thousands of corpses. He was able to separate the ear into its divisional compartments of inner, middle and outer ear.

http://books.google.com.au/books?id=_JDOVMDi8d4C&pg=PA843&lpg=PA843&dq=Gabriele+Falloppio+ear&source=bl&ots=BWTIaLrqRS&sig=BLfW2dTzfmYkZTOGljxCsdCWij4&hl=en&sa=X&ei=gC5oUIb6AoaViAfQx4HYDw&ved=0CDgQ6AEwBDgU#v=snippet&q=%20ear&f=false

===Adult Anatomy and Histology===

<pubmed> 15495168 </pubmed>

<pubmed> 16015653 </pubmed>

<pubmed> 9433684 </pubmed>

===Development===

<pubmed> 6650859 </pubmed>
====Outer Ear====

Historic paper

<pubmed> 17104502 </pubmed>

<pubmed> 22296782 </pubmed>

<pubmed> 12874121 </pubmed>

====Middle Ear====

<pubmed> 18803631 </pubmed>

<pubmed> 21196256 </pubmed>

<pubmed> 14973294 </pubmed>

<pubmed> 11237469 </pubmed>

<pubmed> 16600992 </pubmed>

====Inner Ear====

(can include balance organs as well)
cochlea and semi circular canals and the physiological function - how hearing works

Some papers to start with:

<pubmed>15319325</pubmed>

<pubmed>17891709</pubmed>

<pubmed>10887092</pubmed>

<pubmed>19247974</pubmed>

===Abnormal Hearing===

Just putting my articles in here so I can refer to them at a later date - will change the referencing when I have structured my points better

- DISCUSS CONDUCTIVE AND SNESORINEURAL HEARING LOSS
- ADD PICTURES OF GENETIC TRANSFER
- ADD PICTURE OF LOCATION OF GENE GJB2

Genetic defects:

1. [http://ghr.nlm.nih.gov/gene/GJB2| GJB2 Gene] (accounting for 50% of non syndromic hearing loss)

Environmental

1. Drugs:
Hearing, Speech, Language, and Vestibular Disorders in the Fetal Alcohol Syndrome: A Literature Review. Michael W. Church and James A. Kaltenbach, Alcoholism: Clinical and experimental review. Vol. 21, No. 3, May 1997 [http://www.ncbi.nlm.nih.gov/pubmed/9161611| PMID: 9161611]

2. Infections:
Congenital Rubella Deafness: A preventable disease. C. S Peckham, J. M Martin, W. C Marshall, J. A Dudgeon, The Lancet, February 3, 1979 [http://www.ncbi.nlm.nih.gov/pubmed/84910| PMID: 84910]

[http://www.ncbi.nlm.nih.gov/books/NBK1434/ |Deafness and Hereditary Hearing Loss Overview]

Etiological diagnosis in the hearing impaired newborn: Proposal of a flow chart. De Leenheer, E.M.R. ; Janssens, S. ; Padalko, E. ; Loose, D. ; Leroy, B.P. ; Dhooge, I.J. International Journal of Pediatric Otorhinolaryngology, 2011, Vol.75(1), pp.27-32

[http://sirius.library.unsw.edu.au:9003/sfx_local?frbrVersion=3&ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2012-08-26T10%3A07%3A34IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-sciversesciencedirect_elsevier&rft_val_fmt=info:ofi/fmt:kev:mtx:&rft.genre=article&rft.atitle=Congenital%20cytomegalovirus%20(CMV)%20infection%20as%20a%20cause%20of%20permanent%20bilateral%20hearing%20loss:%20A%20quantitative%20assessment&rft.jtitle=Journal%20of%20Clinical%20Virology&rft.btitle=&rft.aulast=Grosse&rft.auinit=&rft.auinit1=&rft.auinitm=&rft.ausuffix=&rft.au=Grosse%2C%20Scott%20D.&rft.aucorp=&rft.date=2008&rft.volume=41&rft.issue=2&rft.part=&rft.quarter=&rft.ssn=&rft.spage=57&rft.epage=62&rft.pages=57-62&rft.artnum=&rft.issn=1386-6532&rft.eissn=&rft.isbn=&rft.sici=&rft.coden=&rft_id=info:doi/10.1016/j.jcv.2007.09.004&rft.object_id=&svc_val_fmt=info:ofi/fmt:kev:mtx:sch_svc&svc.fulltext=yes&rft_dat=%3Csciversesciencedirect_elsevier%3ES1386-6532(07)00336-8%3C/sciversesciencedirect_elsevier%3E&rft.eisbn=&rft_id=info:oai/%3E| Congenital cytomegalovirus] (CMV) infection as a cause of permanent bilateral hearing loss: A quantitative assessment. Journal of clinical virology [1386-6532] Grosse, Scott yr:2008 vol:41 iss:2 pg:57 -62

Congenital Infections. JF Bale. Neurol Clin. 2002 Nov;20(4):1039-60, vii. [http://www.ncbi.nlm.nih.gov/pubmed/12616680| PMID: 12616680]

Related to both middle and inner ear (so we can link the technologies to this)

===Technologies to detect===
Any technologies (like pre-testing) that identify any problems with hearing development

===Technologies to overcome the problems===
(hearing aids, cochlear transplants, etc)

===Current Research===

===Glossary===

===References===

------------------------------

Allocated subheadings

J: adult anatomy, outer and middle ear development

M: Inner ear

P: History and Technologies

B: Abnormal Hearing

-------------

==Our Thoughts - put new comment at the top please==
Hi guys,

Yes I agree with you M. I have just altered my section, apart from the genetic section, the others all list 3 examples - as we know there are countless ear abnormalities so I thought i would do the same amount of examples for each. I am reading the whole project now to check for the flow and spelling errors if we have any. I will do an introduction in a couple of hours for the abnormalities section!

Thanks, B. [[User:Z3292017|Z3292017]] 13:41, 4 October 2012 (EST)

------
Hey all!

I went through all the references and fixed them up. Also had a look at the layout a little, but I'm pretty happy with the way it is anyways :). I was thinking... we should give ourselves a deadline of FRIDAY 12 NOON (Friday the 5th of October). Do not add, edit or in any way change the page after that. In that case we will not experience any problems when Mark blocks the page :)

M. --[[User:Z3333865|Z3333865]] 07:46, 4 October 2012 (EST)
-------

hey, i was wondering if anyone could help me reference a google book or a book in general

-------
Hey all!

I just put student templates with almost all images, and they should be fine now. The only one that may need editing is the one on the development of the pinna. ALSO(!) do we need a student template if it is a student drawn image?? If any images are uploaded from now on, please just put all the information with it straight away, so we don't have to worry about that anymore :) Thanks guys! M. --[[User:Z3333865|Z3333865]] 16:55, 28 September 2012 (EST)
-------

http://www.sonoworld.com/fetus/page.aspx?id=205 picture of ear at 6 weeks

--[[User:Z3292017|Z3292017]] 11:44, 26 September 2012 (EST)

-------

Hey all! We are starting to get some really good and useful feedback :) Hope everyone is ready to get stuck into editing from tomorrow onwards, cause the project is DUE WED 03/10/2012 - WHICH IS NEXT WEEK!! Keep this in mind. From what I read so far, the aim will be the simplify/reduce our text and include more images. Referencing needs to be fixed as well for some parts of the project.. but all in all its quite good :) M. --[[User:Z3333865|Z3333865]] 09:03, 25 September 2012 (EST)
---------------

Hey! To everyone who is working on the history, please add this to the table! I'm about to change it now so that there is simply one table with significant dates and explanations. And it would be good if we can quickly meet up after one of the lectures tomorrow :) anyone who can't make it, please let the others know. M --[[User:Z3333865|Z3333865]] 14:31, 17 September 2012 (EST)

---------------

Hi P,
How are you going with your research? We really need to have it complete by this weeks lab so that we can spend the next couple of weeks adjusting the information. Thanks, B --[[User:Z3292017|Z3292017]] 12:08, 17 September 2012 (EST)

-------------

Hey M,

Yeah summary sounds like a good idea and maybe wiht some bolded words etc? Ive created 2 tables where I will briefly summarise the remaining diseases such as structural and genetic syndromes as my section will be too long and more boring than what it already is if I keep going. Yes, I think by our next lab would be a good idea. B. --[[User:Z3292017|Z3292017]] 19:22, 15 September 2012 (EST)

-----------

Hey B and others,

My section is almost finished. I mainly have to focus on the images. I was also thinking of putting a summary box in my section, because there is just so much text! About the due date.. I think it will be good for us all to have most of the research and text done by lab 8 (19/09/12). We can then focus on the layout and images and tables, etc. What do you think? M. --[[User:Z3333865|Z3333865]] 17:57, 15 September 2012 (EST)

----------

Hey guys,
I have been updating all of my abnormalities and along with the references, it will all be completed by Sunday night, exempt all the photos as that will be my final research. Thought I would update you all so we can get a finish timeframe in mind!
B. --[[User:Z3292017|Z3292017]] 15:08, 15 September 2012 (EST)
----------

Hi P,
In regards the technologies, you should take a look at my section, because the technologies should really be perhaps how abornal hearing can be detected in the womb (such as amniocentesis for Rubella) and also the different insstruments used for hearing and why they do and don't work on certain patients. and perhaps with the history go a bit more indept/ greater explanation. such as if the first hearing aid was developed, find a picture and say what they originiall used to create noise for the patient etc. Use bulletpoints if you don't want it to seem too full on Do you guys agree?
B. --[[User:Z3292017|Z3292017]] 15:02, 15 September 2012 (EST)
----------

Hey P.
The history section should contain major discoveries and the person(s) of interest. I started writing things down in a table. If anyone find info they should put that in and the original document/article should be referenced if possible (not a review). Hope this helps cause we really have to put all our info together soon. M. --[[User:Z3333865|Z3333865]] 12:40, 14 September 2012 (EST)
----------

Hey guys, for the history, im not 100% what I supposed to write about, i know its late and i'm an idiot for asking now, but am i supposed to write like the old research papers like what they used to think? like how they thought the ear formed like from the 1800's or whatever? and how technologies also helped proved it wrong or proved that they are right? P. --[[User:Z3333431|Z3333431]] 13:13, 12 September 2012 (EST)
------------
DW, I had a look at the editing basics and the references are working now! :) M. --[[User:Z3333865|Z3333865]] 10:20, 3 September 2012 (EST)

----------
Hey ppl!

I can't seem to link my references. '9' and '10' in my inner ear section step 2 should be the same number, but I can't seem to get it to work... can anyone help?

Thanks, M. --[[User:Z3333865|Z3333865]] 09:46, 3 September 2012 (EST)

--------------------

To all,
I find it very difficult to find images which have the correct copyright statement and are not already used on this embryology website.
So if anyone finds an image which we are allowed to use, please post it up and let the others know :)

And to B. That sounds good :) Speak to you tomorrow! M. --[[User:Z3333865|Z3333865]] 13:22, 27 August 2012 (EST)

----------
Hi!

In regards to my abnormalities (we can all discuss further this week), I will be focussing mainly on the gene GJB2 (which accounts for 50% of non syndromic hearing) and then for acquired hearing (organisms), I will focus mainly on what is known as "TORCH" organisms (i.e., toxoplasmosis, rubella, cytomegalic virus, and herpes) and go into details in them and then as M said before, just list the other in a table.

Thanks,
B. --[[User:Z3292017|Z3292017]] 17:45, 26 August 2012 (EST)

----------

Hey!

In regards to the hearing abnormalities, yes I would do the most common ones. It will be way too much otherwise!
Just name the other abnormalities for now - depending on how long your section is we will include them or leave out.
At the end of your section we can also put a table down with a summary of the common ones you explained in detail before :)

M. --[[User:Z3333865|Z3333865]] 13:07, 26 August 2012 (EST)

----------

Hey guys,

Sorry I haven't been communicating via the discussion page, I've been sick in bed with a virus for the past week and half! Anyway, as I am focussing on the hearing abnormalities, I just wanted to clarify some things with you all. Firstly, there are A LOT of genetic disorder which contribute to hearing loss so I was thinking I would group them and would write in depth into the most common ones and then a brief description or just name the others.
I'm currently compiling some research papers, so I will most likely get to writing some points on this page tomorrow.

Let me know if you have any suggestiosn etc and if I find any other articles in my research I will send them through!
--[[User:Z3292017|Z3292017]] 18:44, 25 August 2012 (EST)

----------

Hey all!

For this week, please find some good papers relating to your section - both primary and secondary - and start reading them.
It will take some time to get all the info together and to also make it look good with pictures etc.
So the sooner we start the easier it will be in the long-run!!

--[[User:Z3333865|Z3333865]] 21:00, 18 August 2012 (EST)

----------

Hey everyone!

I guess if we end up doing the sensory topic and focus on the ear we can come up with some headings that we might want to use in our project.

This is the [[Sensory_-_Hearing_and_Balance_Development| link to our lecture on the ear]]

I guess one way of doing this would be to divide it into inner, middle and outer ear and talk about the development of each. I guess we could include the progressive development over the weeks including cellular, molecular and morphological changes. We can also describe the developed ear, any genetic mutations or incorrect signal pathway that cause any defects. Then one part of it can be current research and any past research or noble prizes.

Cheers!

--[[User:Z3333794|Z3333794]] 11:31, 9 August 2012 (EST)

--------------------------------------------
Hey all!

So we have to decide between normal development or abnormal development.
Normal development can have headings as mentioned above, apart from the genetic mutations and defects.
When focussing on abnormal development of the ear we can look at those mutations and defects. We can also look at technology such as hearing aids and the cochlear implant.

Please put down your preference!
I really dont care.. but I think that if we have to discuss development it will be easiest to look at normal development.

--[[User:Z3333865|Z3333865]] 13:06, 14 August 2012 (EST)

2012 Group Project 6

2012-10-04T03:36:57Z

Z3292017: /* Environmental */

[[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'''|| The labyrinth of the ear is discovered. <ref name="PMID11314703"><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 name="PMID11314703"/> [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. <ref name="PMID16269359"><pubmed>16269359</pubmed></ref> <ref><pubmed>11237469</pubmed></ref>

[[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. <ref name="PMID16269359"/>

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. <ref name="PMID16269359"/> <ref><pubmed>21774850</pubmed></ref>

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==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px]]

The development of the outer and middle ear is attributed to the pharyngeal arches one and two. All the germ layer namely endoderm, mesoderm and ectoderm contribute to its formation. <ref><pubmed>8287791</pubmed></ref> The entire inner ear, as well as the neurons which innervate the sensory organ, are derived from the otic placode. <ref name="PMID17891709"><pubmed>17891709</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 and middle ear structures. 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. <ref><pubmed>11698185</pubmed></ref> 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.<ref name="PMID17891709"/> This will form an otic vesicle (otocyst) and further develop into the structures of the inner ear.

We will consider the outer, middle and inner ear separately.

===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 name="PMID10976045"><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 name="PMID10976045"/> <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.<ref name="PMID17891709"/>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"/>[[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>
[[File:z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared]]

'''2''' ''Pre-otic field''

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"/>
[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]

'''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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle]]

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'''
[[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>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them. <ref><pubmed>22778034</pubmed></ref>

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.<ref><pubmed>12530227</pubmed></ref> It exits through the internal acoustic meatus (IAM) to conduct signals to the brain for processing.

====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 name="PMID10980526"><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 name="PMID10980526"/>.
* 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>PMC3335728</pubmed></ref>.

|}

'''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
* Usher Syndrome predominantly affects the outer hair cells in the cochlear. Cochlear implants have given great improvements in both hearing and quality of life in these patients.
* 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 classic structural deformity is Mondini dysplasia of the cochlear whereby the cochlear is not complete having less than the required two and a half turns <ref><pubmed>3776519</pubmed></ref>.
* 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>.

||
[[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. It was also identified that 15 of the 23,000 pregnancies vertical transmission of the child contracting congenital toxoplasmosis <ref name="PMID3041362"><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* Detection of toxoplasmosis is achived through amniocentesis and subsequently using PCR to determine a positive result from DNA amplification <ref name="PMID3041362"/>.
* 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>. However inconclusive and inconsistent treatment investigations suggested to be caused by limited randomised controlled trials <ref><pubmed> 9988811 </pubmed></ref>.

|- bgcolor="#AAF0D1"
|''Rubella'' ||
* In 1979 an article provided evidence of the direct link between rubella and sensorineural deafness finding 24% of the hearing impaired children tested had the rubella antibody <ref><pubmed>84910</pubmed></ref>.
* Fetal infection risk will differ throughout the duration of the pregnancy. Week 1 to 10 has 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. There is a dramatic decrease in the second and third trimester (due to maternal antibodies and fetal cell mediated immune responses) however it goes back to 100% in the last month of pregnancy.
*Rubella infects the placenta via maternal viraemia which leads to necrotic areas in the chorionic villae epithelium <ref><pubmed>5949097</pubmed></ref>. It is thought that the rubella virus is passed through the fetal circulation via endothelial cell emboli. <ref><pubmed>2817948</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* It is an entirely preventable disease through the Rubella vaccine, being almost completely eliminated in western countries.

|- 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.
* Two 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 <ref><pubmed>3067168</pubmed></ref>
# 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''Drugs'''

{| cellpadding=5 style="border:1px solid #FF0090"
|- bgcolor="#FF55A3"
|'''Drug'''||'''Description'''
|- bgcolor="#FFF0F5"
|''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 <ref name="PMID9161611"><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 greater amount of apoptosis during the inner ear development and thus decreased growth of neurons and myelin and subsequently the synapses. Intermittent conductive hearing loss is thought to be due to poorly formed eustachian tube <ref><pubmed>12795509</pubmed></ref>.
* The central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing <ref name="PMID9161611"/>.

|- bgcolor="#FFA6C9"
|''Isotretinoin'' ||
* Isotretinoin is a treatment option for patients with severe cystic acne.
* It is teratogenic and its associated congenital malformations include: Lack of ears and malformations of the inner, middle and outer ears, along with mental retardations, facial malformations and heart and limb defects. <ref><pubmed>PMC1859978</pubmed></ref>.
* This is thought to be due to the ear not reaching full development such as the Mondini malformation.
* The most severe inner ear abnormalities occur when the mother was taking isotretinoin during the gastrulation stage, with the abnormalities indicating that the development was interrupted. It is thought that this is due to the disruption of the neural crest cell population. <ref><pubmed>1440418</pubmed></ref>

|- bgcolor="#FFF0F5"
|''Thalidomide'' ||
* Thalidomide was a drug used to ease morning sickness symptoms in the 1950's and 1960's until it was found to be teratogenic.
* Known for its limb reduction abnormalities, it also contributes to outer and inner ear malformations and heart and eye defects.
* Critical time periods for exposure to Thalidomide for outer ear malformations was days 20-24 post fertilisation and inner ear from day 24-34.
* Thalidomide is thought to increase the oxygen radical formation which generates oxidative stress along with inhibiting angiogenesis <ref><pubmed>21507989</pubmed></ref>.
|}

===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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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 - Auditory Brainstem Response test]]

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===
[[File:Hearing_aids.JPG|thumb|200 px|right| 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 amplification 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 amplification 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 amplifier. The amplifier sends the impulses though the speaker into the ear as an increased sound.
<ref>National Institute of Health, '''Hearing Aid Basics''', http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx, Access date 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>6028666</pubmed></ref>

[[File:Cochlear_Implant.jpg|x250px|Cochlear Implant]]

==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

*'''Nonsyndromic deafness''': Hearing impairment not affiliated with other signs or symptoms

*'''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

*'''Syndromic deafness''': Hearing impairment occurring with additional abnormalities in the body

*'''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

== References ==
<references/>

==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]

{{External Links}}

==Image Gallery==

<gallery>

Image: Anatomy_of_the_Ear.JPG|thumb|left|350px|Anatomy of the ear
Image: Histology_of_Inner_Ear.png|thumb|right|300px|Histology of Inner Ear
Image: Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px|Pharyngeal arches one and two in mice embryo
Image: Devt_of_external_ear.JPG|thumb|400px|The image depicts the development of the pinna through the fetal development stages
Image: normal cochlea.png |thumb|150px|Wild-type inner ear showing normal morphology
Image: z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared
Image: otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo
Image: neural fate.jpg|thumb|200px|Recent model related to sensory fate.
Image: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle
Image: z3333865.gene expression.jpeg|thumb|300px|Representative expression patterns of genes controlling cochlear and vestibular specification.
Image: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea
Image: Dominant_diagram.jpg|x250px
Image: Autosomal_Recessive_Inheritance_Diagram.jpg|x250px
Image: X_Linked_Recessive_Diagram.jpg|x250px
Image: Pendred_Syndrome_Showing_Mondini_Defects.jpg|x450px
Image: MRI_of_Goldenhar_Syndrome.jpg
Image: Bilateral_Stenosis_of_Internal_Auditory_canal.jpg|x230px
Image: Enlarged_Vestibular_aqueduct.jpg|x250p
Image: Microtia_boy_surgery.jpg|x320px]
Image: Infant hearing test.jpg|thumb|300px|Testing the hearing of an infant - Auditory Brainstem Response test
Image: Cochlear_Implant.jpg|x250px|Cochlear Implant
Image: Atoh1 model.png|left|thumb|225px|Atoh1-cre is expressed in hair cells and causes transient limited expression of Atoh1 in CKO ears
Image: 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.

</gallery>

--[[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

2012-10-04T03:34:57Z

Z3292017: /* Environmental */

[[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'''|| The labyrinth of the ear is discovered. <ref name="PMID11314703"><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 name="PMID11314703"/> [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. <ref name="PMID16269359"><pubmed>16269359</pubmed></ref> <ref><pubmed>11237469</pubmed></ref>

[[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. <ref name="PMID16269359"/>

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. <ref name="PMID16269359"/> <ref><pubmed>21774850</pubmed></ref>

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==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px]]

The development of the outer and middle ear is attributed to the pharyngeal arches one and two. All the germ layer namely endoderm, mesoderm and ectoderm contribute to its formation. <ref><pubmed>8287791</pubmed></ref> The entire inner ear, as well as the neurons which innervate the sensory organ, are derived from the otic placode. <ref name="PMID17891709"><pubmed>17891709</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 and middle ear structures. 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. <ref><pubmed>11698185</pubmed></ref> 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.<ref name="PMID17891709"/> This will form an otic vesicle (otocyst) and further develop into the structures of the inner ear.

We will consider the outer, middle and inner ear separately.

===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 name="PMID10976045"><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 name="PMID10976045"/> <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.<ref name="PMID17891709"/>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"/>[[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>
[[File:z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared]]

'''2''' ''Pre-otic field''

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"/>
[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]

'''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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle]]

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'''
[[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>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them. <ref><pubmed>22778034</pubmed></ref>

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.<ref><pubmed>12530227</pubmed></ref> It exits through the internal acoustic meatus (IAM) to conduct signals to the brain for processing.

====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 name="PMID10980526"><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 name="PMID10980526"/>.
* 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>PMC3335728</pubmed></ref>.

|}

'''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
* Usher Syndrome predominantly affects the outer hair cells in the cochlear. Cochlear implants have given great improvements in both hearing and quality of life in these patients.
* 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 classic structural deformity is Mondini dysplasia of the cochlear whereby the cochlear is not complete having less than the required two and a half turns <ref><pubmed>3776519</pubmed></ref>.
* 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>.

||
[[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. It was also identified that 15 of the 23,000 pregnancies vertical transmission of the child contracting congenital toxoplasmosis <ref name="PMID3041362"><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* Detection of toxoplasmosis is achived through amniocentesis and subsequently using PCR to determine a positive result from DNA amplification <ref name="PMID3041362"/>.
* 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>. However inconclusive and inconsistent treatment investigations suggested to be caused by limited randomised controlled trials <ref><pubmed> 9988811 </pubmed></ref>.

|- bgcolor="#AAF0D1"
|''Rubella'' ||
* In 1979 an article provided evidence of the direct link between rubella and sensorineural deafness finding 24% of the hearing impaired children tested had the rubella antibody <ref><pubmed>84910</pubmed></ref>.
* Fetal infection risk will differ throughout the duration of the pregnancy. Week 1 to 10 has 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. There is a dramatic decrease in the second and third trimester (due to maternal antibodies and fetal cell mediated immune responses) however it goes back to 100% in the last month of pregnancy.
*Rubella infects the placenta via maternal viraemia which leads to necrotic areas in the chorionic villae epithelium <ref><pubmed>5949097</pubmed></ref>. It is thought that the rubella virus is passed through the fetal circulation via endothelial cell emboli. <ref><pubmed>2817948</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* It is an entirely preventable disease through the Rubella vaccine, being almost completely eliminated in western countries.

|- 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.
* Two 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 <ref><pubmed>3067168</pubmed></ref>
# 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''Drugs'''

{| cellpadding=5 style="border:1px solid #FF0090"
|- bgcolor="#FF55A3"
|'''Drug'''||'''Description'''
|- bgcolor="#FFF0F5"
|''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 <ref name="PMID9161611"><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 greater amount of apoptosis during the inner ear development and thus decreased growth of neurons and myelin and subsequently the synapses. Intermittent conductive hearing loss is thought to be due to poorly formed eustachian tube <ref><pubmed>12795509</pubmed></ref>.
* The central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing <ref name="PMID9161611"/>.

|- bgcolor="#FFA6C9"
|''Isotretinoin'' ||
* Isotretinoin is a treatment option for patients with severe cystic acne.
* It is teratogenic and its associated congenital malformations include: Lack of ears and malformations of the inner, middle and outer ears, along with mental retardations, facial malformations and heart and limb defects. <ref><pubmed>PMC1859978</pubmed></ref>.
* This is thought to be due to the ear not reaching full development such as the Mondini malformation.
* The most severe inner ear abnormalities occur when the mother was taking isotretinoin during the gastrulation stage, with the abnormalities indicating that the development was interrupted. It is thought that this is due to the disruption of the neural crest cell population. <ref><pubmed>1440418</pubmed></ref>

|- bgcolor="#FFF0F5"
|''Thalidomide'' ||
* Thalidomide was a drug used to ease morning sickness symptoms in the 1950's and 1960's until it was found to be teratogenic.
* Known for its limb reduction abnormalities, it also contributes to outer and inner ear malformations and heart and eye defects.
* Critical time periods for exposure to Thalidomide for outer ear malformations was days 20-24 post fertilisation and inner ear from day 24-34.
* Thalidomide is thought to increase the oxygen radical formation which generates oxidative stress along with inhibiting angiogenesis <ref><pubmed>21507989</pubmed></ref>.
|}

===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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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 - Auditory Brainstem Response test]]

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===
[[File:Hearing_aids.JPG|thumb|200 px|right| 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 amplification 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 amplification 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 amplifier. The amplifier sends the impulses though the speaker into the ear as an increased sound.
<ref>National Institute of Health, '''Hearing Aid Basics''', http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx, Access date 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>6028666</pubmed></ref>

[[File:Cochlear_Implant.jpg|x250px|Cochlear Implant]]

==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

*'''Nonsyndromic deafness''': Hearing impairment not affiliated with other signs or symptoms

*'''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

*'''Syndromic deafness''': Hearing impairment occurring with additional abnormalities in the body

*'''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

== References ==
<references/>

==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]

{{External Links}}

==Image Gallery==

<gallery>

Image: Anatomy_of_the_Ear.JPG|thumb|left|350px|Anatomy of the ear
Image: Histology_of_Inner_Ear.png|thumb|right|300px|Histology of Inner Ear
Image: Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px|Pharyngeal arches one and two in mice embryo
Image: Devt_of_external_ear.JPG|thumb|400px|The image depicts the development of the pinna through the fetal development stages
Image: normal cochlea.png |thumb|150px|Wild-type inner ear showing normal morphology
Image: z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared
Image: otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo
Image: neural fate.jpg|thumb|200px|Recent model related to sensory fate.
Image: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle
Image: z3333865.gene expression.jpeg|thumb|300px|Representative expression patterns of genes controlling cochlear and vestibular specification.
Image: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea
Image: Dominant_diagram.jpg|x250px
Image: Autosomal_Recessive_Inheritance_Diagram.jpg|x250px
Image: X_Linked_Recessive_Diagram.jpg|x250px
Image: Pendred_Syndrome_Showing_Mondini_Defects.jpg|x450px
Image: MRI_of_Goldenhar_Syndrome.jpg
Image: Bilateral_Stenosis_of_Internal_Auditory_canal.jpg|x230px
Image: Enlarged_Vestibular_aqueduct.jpg|x250p
Image: Microtia_boy_surgery.jpg|x320px]
Image: Infant hearing test.jpg|thumb|300px|Testing the hearing of an infant - Auditory Brainstem Response test
Image: Cochlear_Implant.jpg|x250px|Cochlear Implant
Image: Atoh1 model.png|left|thumb|225px|Atoh1-cre is expressed in hair cells and causes transient limited expression of Atoh1 in CKO ears
Image: 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.

</gallery>

--[[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

2012-10-04T03:22:01Z

Z3292017: /* Environmental */

[[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'''|| The labyrinth of the ear is discovered. <ref name="PMID11314703"><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 name="PMID11314703"/> [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. <ref name="PMID16269359"><pubmed>16269359</pubmed></ref> <ref><pubmed>11237469</pubmed></ref>

[[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. <ref name="PMID16269359"/>

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. <ref name="PMID16269359"/> <ref><pubmed>21774850</pubmed></ref>

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==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px]]

The development of the outer and middle ear is attributed to the pharyngeal arches one and two. All the germ layer namely endoderm, mesoderm and ectoderm contribute to its formation. <ref><pubmed>8287791</pubmed></ref> The entire inner ear, as well as the neurons which innervate the sensory organ, are derived from the otic placode. <ref name="PMID17891709"><pubmed>17891709</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 and middle ear structures. 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. <ref><pubmed>11698185</pubmed></ref> 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.<ref name="PMID17891709"/> This will form an otic vesicle (otocyst) and further develop into the structures of the inner ear.

We will consider the outer, middle and inner ear separately.

===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 name="PMID10976045"><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 name="PMID10976045"/> <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.<ref name="PMID17891709"/>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"/>[[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>
[[File:z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared]]

'''2''' ''Pre-otic field''

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"/>
[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]

'''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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle]]

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'''
[[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>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them. <ref><pubmed>22778034</pubmed></ref>

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.<ref><pubmed>12530227</pubmed></ref> It exits through the internal acoustic meatus (IAM) to conduct signals to the brain for processing.

====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 name="PMID10980526"><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 name="PMID10980526"/>.
* 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>PMC3335728</pubmed></ref>.

|}

'''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
* Usher Syndrome predominantly affects the outer hair cells in the cochlear. Cochlear implants have given great improvements in both hearing and quality of life in these patients.
* 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 classic structural deformity is Mondini dysplasia of the cochlear whereby the cochlear is not complete having less than the required two and a half turns <ref><pubmed>3776519</pubmed></ref>.
* 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>.

||
[[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. It was also identified that 15 of the 23,000 pregnancies vertical transmission of the child contracting congenital toxoplasmosis <ref name="PMID3041362"><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* Detection of toxoplasmosis is achived through amniocentesis and subsequently using PCR to determine a positive result from DNA amplification <ref name="PMID3041362"/>.
* 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>. However inconclusive and inconsistent treatment investigations suggested to be caused by limited randomised controlled trials <ref><pubmed> 9988811 </pubmed></ref>.

|- bgcolor="#AAF0D1"
|''Rubella'' ||
* In 1979 an article provided evidence of the direct link between rubella and sensorineural deafness finding 24% of the hearing impaired children tested had the rubella antibody <ref><pubmed>84910</pubmed></ref>.
* Fetal infection risk will differ throughout the duration of the pregnancy. Week 1 to 10 has 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. There is a dramatic decrease in the second and third trimester (due to maternal antibodies and fetal cell mediated immune responses) however it goes back to 100% in the last month of pregnancy.
*Rubella infects the placenta via maternal viraemia which leads to necrotic areas in the chorionic villae epithelium <ref><pubmed>5949097</pubmed></ref>. It is thought that the rubella virus is passed through the fetal circulation via endothelial cell emboli. <ref><pubmed>2817948</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* It is an entirely preventable disease through the Rubella vaccine, being almost completely eliminated in western countries.

|- 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.
* Two 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 <ref><pubmed>3067168</pubmed></ref>
# 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''Drugs'''

{| cellpadding=5 style="border:1px solid #FF0090"
|- bgcolor="#FF55A3"
|'''Drug'''||'''Description'''
|- bgcolor="#FFF0F5"
|''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 <ref name="PMID9161611"><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 greater amount of apoptosis during the inner ear development and thus decreased growth of neurons and myelin and subsequently the synapses. Intermittent conductive hearing loss is thought to be due to poorly formed eustachian tube <ref><pubmed>12795509</pubmed></ref>.
* The central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing <ref name="PMID9161611"/>.

|- bgcolor="#FFA6C9"
|''Isotretinoin'' ||
* Isotretinoin is a treatment option for patients with severe cystic acne.
* It is teratogenic and its associated congenital malformations include: Lack of ears and malformations of the inner, middle and outer ears, along with mental retardations, facial malformations and heart and limb defects. <ref><pubmed>PMC1859978</pubmed></ref>.
* This is thought to be due to the ear not reaching full development such as the Mondini malformation.
* The most severe inner ear abnormalities occur when the mother was taking isotretinoin during the gastrulation stage, with the abnormalities indicating that the development was interrupted. It is thought that this is due to the disruption of the neural crest cell population. <ref><pubmed>1440418</pubmed></ref>

|- bgcolor="#FFF0F5"
|''Thalidomide'' ||
|}

===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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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 - Auditory Brainstem Response test]]

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===
[[File:Hearing_aids.JPG|thumb|200 px|right| 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 amplification 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 amplification 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 amplifier. The amplifier sends the impulses though the speaker into the ear as an increased sound.
<ref>National Institute of Health, '''Hearing Aid Basics''', http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx, Access date 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>6028666</pubmed></ref>

[[File:Cochlear_Implant.jpg|x250px|Cochlear Implant]]

==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

*'''Nonsyndromic deafness''': Hearing impairment not affiliated with other signs or symptoms

*'''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

*'''Syndromic deafness''': Hearing impairment occurring with additional abnormalities in the body

*'''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

== References ==
<references/>

==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]

{{External Links}}

==Image Gallery==

<gallery>

Image: Anatomy_of_the_Ear.JPG|thumb|left|350px|Anatomy of the ear
Image: Histology_of_Inner_Ear.png|thumb|right|300px|Histology of Inner Ear
Image: Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px|Pharyngeal arches one and two in mice embryo
Image: Devt_of_external_ear.JPG|thumb|400px|The image depicts the development of the pinna through the fetal development stages
Image: normal cochlea.png |thumb|150px|Wild-type inner ear showing normal morphology
Image: z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared
Image: otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo
Image: neural fate.jpg|thumb|200px|Recent model related to sensory fate.
Image: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle
Image: z3333865.gene expression.jpeg|thumb|300px|Representative expression patterns of genes controlling cochlear and vestibular specification.
Image: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea
Image: Dominant_diagram.jpg|x250px
Image: Autosomal_Recessive_Inheritance_Diagram.jpg|x250px
Image: X_Linked_Recessive_Diagram.jpg|x250px
Image: Pendred_Syndrome_Showing_Mondini_Defects.jpg|x450px
Image: MRI_of_Goldenhar_Syndrome.jpg
Image: Bilateral_Stenosis_of_Internal_Auditory_canal.jpg|x230px
Image: Enlarged_Vestibular_aqueduct.jpg|x250p
Image: Microtia_boy_surgery.jpg|x320px]
Image: Infant hearing test.jpg|thumb|300px|Testing the hearing of an infant - Auditory Brainstem Response test
Image: Cochlear_Implant.jpg|x250px|Cochlear Implant
Image: Atoh1 model.png|left|thumb|225px|Atoh1-cre is expressed in hair cells and causes transient limited expression of Atoh1 in CKO ears
Image: 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.

</gallery>

--[[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

2012-10-04T03:14:40Z

Z3292017: /* Environmental */

[[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'''|| The labyrinth of the ear is discovered. <ref name="PMID11314703"><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 name="PMID11314703"/> [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. <ref name="PMID16269359"><pubmed>16269359</pubmed></ref> <ref><pubmed>11237469</pubmed></ref>

[[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. <ref name="PMID16269359"/>

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. <ref name="PMID16269359"/> <ref><pubmed>21774850</pubmed></ref>

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==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px]]

The development of the outer and middle ear is attributed to the pharyngeal arches one and two. All the germ layer namely endoderm, mesoderm and ectoderm contribute to its formation. <ref><pubmed>8287791</pubmed></ref> The entire inner ear, as well as the neurons which innervate the sensory organ, are derived from the otic placode. <ref name="PMID17891709"><pubmed>17891709</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 and middle ear structures. 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. <ref><pubmed>11698185</pubmed></ref> 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.<ref name="PMID17891709"/> This will form an otic vesicle (otocyst) and further develop into the structures of the inner ear.

We will consider the outer, middle and inner ear separately.

===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 name="PMID10976045"><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 name="PMID10976045"/> <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.<ref name="PMID17891709"/>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"/>[[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>
[[File:z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared]]

'''2''' ''Pre-otic field''

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"/>
[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]

'''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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle]]

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'''
[[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>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them. <ref><pubmed>22778034</pubmed></ref>

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.<ref><pubmed>12530227</pubmed></ref> It exits through the internal acoustic meatus (IAM) to conduct signals to the brain for processing.

====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 name="PMID10980526"><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 name="PMID10980526"/>.
* 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>PMC3335728</pubmed></ref>.

|}

'''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
* Usher Syndrome predominantly affects the outer hair cells in the cochlear. Cochlear implants have given great improvements in both hearing and quality of life in these patients.
* 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 classic structural deformity is Mondini dysplasia of the cochlear whereby the cochlear is not complete having less than the required two and a half turns <ref><pubmed>3776519</pubmed></ref>.
* 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>.

||
[[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. It was also identified that 15 of the 23,000 pregnancies vertical transmission of the child contracting congenital toxoplasmosis <ref name="PMID3041362"><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* Detection of toxoplasmosis is achived through amniocentesis and subsequently using PCR to determine a positive result from DNA amplification <ref name="PMID3041362"/>.
* 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>. However inconclusive and inconsistent treatment investigations suggested to be caused by limited randomised controlled trials <ref><pubmed> 9988811 </pubmed></ref>.

|- bgcolor="#AAF0D1"
|''Rubella'' ||
* In 1979 an article provided evidence of the direct link between rubella and sensorineural deafness finding 24% of the hearing impaired children tested had the rubella antibody <ref><pubmed>84910</pubmed></ref>.
* Fetal infection risk will differ throughout the duration of the pregnancy. Week 1 to 10 has 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. There is a dramatic decrease in the second and third trimester (due to maternal antibodies and fetal cell mediated immune responses) however it goes back to 100% in the last month of pregnancy.
*Rubella infects the placenta via maternal viraemia which leads to necrotic areas in the chorionic villae epithelium <ref><pubmed>5949097</pubmed></ref>. It is thought that the rubella virus is passed through the fetal circulation via endothelial cell emboli. <ref><pubmed>2817948</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* It is an entirely preventable disease through the Rubella vaccine, being almost completely eliminated in western countries.

|- 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.
* Two 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 <ref><pubmed>3067168</pubmed></ref>
# 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''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 <ref name="PMID9161611"><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 greater amount of apoptosis during the inner ear development and thus decreased growth of neurons and myelin and subsequently the synapses. Intermittent conductive hearing loss is thought to be due to poorly formed eustachian tube <ref><pubmed>12795509</pubmed></ref>.
* The central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing <ref name="PMID9161611"/>.

|- bgcolor="#FFF0F5"
|''Isotretinoin'' ||
* Isotretinoin is a treatment option for patients with severe cystic acne.
* It is teratogenic and its associated congenital malformations include: Lack of ears and malformations of the inner, middle and outer ears, along with mental retardations, facial malformations and heart and limb defects. <ref><pubmed>PMC1859978</pubmed></ref>.
* This is thought to be due to the ear not reaching full development such as the Mondini malformation.
* The most severe inner ear abnormalities occur when the mother was taking isotretinoin during the gastrulation stage, with the abnormalities indicating that the development was interrupted. It is thought that this is due to the disruption of the neural crest cell population. <ref><pubmed>1440418</pubmed></ref>

|}

===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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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 - Auditory Brainstem Response test]]

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===
[[File:Hearing_aids.JPG|thumb|200 px|right| 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 amplification 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 amplification 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 amplifier. The amplifier sends the impulses though the speaker into the ear as an increased sound.
<ref>National Institute of Health, '''Hearing Aid Basics''', http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx, Access date 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>6028666</pubmed></ref>

[[File:Cochlear_Implant.jpg|x250px|Cochlear Implant]]

==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

*'''Nonsyndromic deafness''': Hearing impairment not affiliated with other signs or symptoms

*'''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

*'''Syndromic deafness''': Hearing impairment occurring with additional abnormalities in the body

*'''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

== References ==
<references/>

==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]

{{External Links}}

==Image Gallery==

<gallery>

Image: Anatomy_of_the_Ear.JPG|thumb|left|350px|Anatomy of the ear
Image: Histology_of_Inner_Ear.png|thumb|right|300px|Histology of Inner Ear
Image: Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px|Pharyngeal arches one and two in mice embryo
Image: Devt_of_external_ear.JPG|thumb|400px|The image depicts the development of the pinna through the fetal development stages
Image: normal cochlea.png |thumb|150px|Wild-type inner ear showing normal morphology
Image: z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared
Image: otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo
Image: neural fate.jpg|thumb|200px|Recent model related to sensory fate.
Image: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle
Image: z3333865.gene expression.jpeg|thumb|300px|Representative expression patterns of genes controlling cochlear and vestibular specification.
Image: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea
Image: Dominant_diagram.jpg|x250px
Image: Autosomal_Recessive_Inheritance_Diagram.jpg|x250px
Image: X_Linked_Recessive_Diagram.jpg|x250px
Image: Pendred_Syndrome_Showing_Mondini_Defects.jpg|x450px
Image: MRI_of_Goldenhar_Syndrome.jpg
Image: Bilateral_Stenosis_of_Internal_Auditory_canal.jpg|x230px
Image: Enlarged_Vestibular_aqueduct.jpg|x250p
Image: Microtia_boy_surgery.jpg|x320px]
Image: Infant hearing test.jpg|thumb|300px|Testing the hearing of an infant - Auditory Brainstem Response test
Image: Cochlear_Implant.jpg|x250px|Cochlear Implant
Image: Atoh1 model.png|left|thumb|225px|Atoh1-cre is expressed in hair cells and causes transient limited expression of Atoh1 in CKO ears
Image: 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.

</gallery>

--[[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

2012-10-04T01:26:20Z

Z3292017: /* Environmental */

[[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'''|| The labyrinth of the ear is discovered. <ref name="PMID11314703"><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 name="PMID11314703"/> [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. <ref name="PMID16269359"><pubmed>16269359</pubmed></ref> <ref><pubmed>11237469</pubmed></ref>

[[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. <ref name="PMID16269359"/>

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. <ref name="PMID16269359"/> <ref><pubmed>21774850</pubmed></ref>

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==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px]]

The development of the outer and middle ear is attributed to the pharyngeal arches one and two. All the germ layer namely endoderm, mesoderm and ectoderm contribute to its formation. <ref><pubmed>8287791</pubmed></ref> The entire inner ear, as well as the neurons which innervate the sensory organ, are derived from the otic placode. <ref name="PMID17891709"><pubmed>17891709</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 and middle ear structures. 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. <ref><pubmed>11698185</pubmed></ref> 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.<ref name="PMID17891709"/> This will form an otic vesicle (otocyst) and further develop into the structures of the inner ear.

We will consider the outer, middle and inner ear separately.

===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 name="PMID10976045"><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 name="PMID10976045"/> <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.<ref name="PMID17891709"/>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"/>[[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>
[[File:z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared]]

'''2''' ''Pre-otic field''

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"/>
[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]

'''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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle]]

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'''
[[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>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them. <ref><pubmed>22778034</pubmed></ref>

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.<ref><pubmed>12530227</pubmed></ref> It exits through the internal acoustic meatus (IAM) to conduct signals to the brain for processing.

====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 name="PMID10980526"><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 name="PMID10980526"/>.
* 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>PMC3335728</pubmed></ref>.

|}

'''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
* Usher Syndrome predominantly affects the outer hair cells in the cochlear. Cochlear implants have given great improvements in both hearing and quality of life in these patients.
* 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 classic structural deformity is Mondini dysplasia of the cochlear whereby the cochlear is not complete having less than the required two and a half turns <ref><pubmed>3776519</pubmed></ref>.
* 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>.

||
[[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. It was also identified that 15 of the 23,000 pregnancies vertical transmission of the child contracting congenital toxoplasmosis <ref name="PMID3041362"><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* Detection of toxoplasmosis is achived through amniocentesis and subsequently using PCR to determine a positive result from DNA amplification <ref name="PMID3041362"/>.
* 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>. However inconclusive and inconsistent treatment investigations suggested to be caused by limited randomised controlled trials <ref><pubmed> 9988811 </pubmed></ref>.

|- bgcolor="#AAF0D1"
|''Rubella'' ||
* In 1979 an article provided evidence of the direct link between rubella and sensorineural deafness finding 24% of the hearing impaired children tested had the rubella antibody <ref><pubmed>84910</pubmed></ref>.
* Fetal infection risk will differ throughout the duration of the pregnancy. Week 1 to 10 has 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. There is a dramatic decrease in the second and third trimester (due to maternal antibodies and fetal cell mediated immune responses) however it goes back to 100% in the last month of pregnancy.
*Rubella infects the placenta via maternal viraemia which leads to necrotic areas in the chorionic villae epithelium <ref><pubmed>5949097</pubmed></ref>. It is thought that the rubella virus is passed through the fetal circulation via endothelial cell emboli. <ref><pubmed>2817948</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* It is an entirely preventable disease through the Rubella vaccine, being almost completely eliminated in western countries.

|- 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.
* Two 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 <ref><pubmed>3067168</pubmed></ref>
# 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''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 <ref name="PMID9161611"><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 greater amount of apoptosis during the inner ear development and thus decreased growth of neurons and myelin and subsequently the synapses. Intermittent conductive hearing loss is thought to be due to poorly formed eustachian tube <ref><pubmed>12795509</pubmed></ref>.
* The central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing <ref name="PMID9161611"/>.

|- 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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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 - Auditory Brainstem Response test]]

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===
[[File:Hearing_aids.JPG|thumb|200 px|right| 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 amplification 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 amplification 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 amplifier. The amplifier sends the impulses though the speaker into the ear as an increased sound.
<ref>National Institute of Health, '''Hearing Aid Basics''', http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx, Access date 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>6028666</pubmed></ref>

[[File:Cochlear_Implant.jpg|x250px|Cochlear Implant]]

==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

*'''Nonsyndromic deafness''': Hearing impairment not affiliated with other signs or symptoms

*'''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

*'''Syndromic deafness''': Hearing impairment occurring with additional abnormalities in the body

*'''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

== References ==
<references/>

==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]

{{External Links}}

==Image Gallery==

<gallery>

Image: Anatomy_of_the_Ear.JPG|thumb|left|350px|Anatomy of the ear
Image: Histology_of_Inner_Ear.png|thumb|right|300px|Histology of Inner Ear
Image: Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px|Pharyngeal arches one and two in mice embryo
Image: Devt_of_external_ear.JPG|thumb|400px|The image depicts the development of the pinna through the fetal development stages
Image: normal cochlea.png |thumb|150px|Wild-type inner ear showing normal morphology
Image: z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared
Image: otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo
Image: neural fate.jpg|thumb|200px|Recent model related to sensory fate.
Image: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle
Image: z3333865.gene expression.jpeg|thumb|300px|Representative expression patterns of genes controlling cochlear and vestibular specification.
Image: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea
Image: Dominant_diagram.jpg|x250px
Image: Autosomal_Recessive_Inheritance_Diagram.jpg|x250px
Image: X_Linked_Recessive_Diagram.jpg|x250px
Image: Pendred_Syndrome_Showing_Mondini_Defects.jpg|x450px
Image: MRI_of_Goldenhar_Syndrome.jpg
Image: Bilateral_Stenosis_of_Internal_Auditory_canal.jpg|x230px
Image: Enlarged_Vestibular_aqueduct.jpg|x250p
Image: Microtia_boy_surgery.jpg|x320px]
Image: Infant hearing test.jpg|thumb|300px|Testing the hearing of an infant - Auditory Brainstem Response test
Image: Cochlear_Implant.jpg|x250px|Cochlear Implant
Image: Atoh1 model.png|left|thumb|225px|Atoh1-cre is expressed in hair cells and causes transient limited expression of Atoh1 in CKO ears
Image: 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.

</gallery>

--[[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

2012-10-04T01:14:24Z

Z3292017: /* Environmental */

[[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'''|| The labyrinth of the ear is discovered. <ref name="PMID11314703"><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 name="PMID11314703"/> [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. <ref name="PMID16269359"><pubmed>16269359</pubmed></ref> <ref><pubmed>11237469</pubmed></ref>

[[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. <ref name="PMID16269359"/>

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. <ref name="PMID16269359"/> <ref><pubmed>21774850</pubmed></ref>

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==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px]]

The development of the outer and middle ear is attributed to the pharyngeal arches one and two. All the germ layer namely endoderm, mesoderm and ectoderm contribute to its formation. <ref><pubmed>8287791</pubmed></ref> The entire inner ear, as well as the neurons which innervate the sensory organ, are derived from the otic placode. <ref name="PMID17891709"><pubmed>17891709</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 and middle ear structures. 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. <ref><pubmed>11698185</pubmed></ref> 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.<ref name="PMID17891709"/> This will form an otic vesicle (otocyst) and further develop into the structures of the inner ear.

We will consider the outer, middle and inner ear separately.

===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 name="PMID10976045"><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 name="PMID10976045"/> <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.<ref name="PMID17891709"/>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"/>[[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>
[[File:z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared]]

'''2''' ''Pre-otic field''

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"/>
[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]

'''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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle]]

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'''
[[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>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them. <ref><pubmed>22778034</pubmed></ref>

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.<ref><pubmed>12530227</pubmed></ref> It exits through the internal acoustic meatus (IAM) to conduct signals to the brain for processing.

====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 name="PMID10980526"><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 name="PMID10980526"/>.
* 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>PMC3335728</pubmed></ref>.

|}

'''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
* Usher Syndrome predominantly affects the outer hair cells in the cochlear. Cochlear implants have given great improvements in both hearing and quality of life in these patients.
* 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 classic structural deformity is Mondini dysplasia of the cochlear whereby the cochlear is not complete having less than the required two and a half turns <ref><pubmed>3776519</pubmed></ref>.
* 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>.

||
[[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. It was also identified that 15 of the 23,000 pregnancies vertical transmission of the child contracting congenital toxoplasmosis <ref name="PMID3041362"><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* Detection of toxoplasmosis is achived through amniocentesis and subsequently using PCR to determine a positive result from DNA amplification <ref name="PMID3041362"/>.
* 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>. However inconclusive and inconsistent treatment investigations suggested to be caused by limited randomised controlled trials <ref><pubmed> 9988811 </pubmed></ref>.

|- bgcolor="#AAF0D1"
|''Rubella'' ||
* In 1979 an article provided evidence of the direct link between rubella and sensorineural deafness finding 24% of the hearing impaired children tested had the rubella antibody <ref><pubmed>84910</pubmed></ref>.
* Fetal infection risk will differ throughout the duration of the pregnancy. Week 1 to 10 has 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. There is a dramatic decrease in the second and third trimester (due to maternal antibodies and fetal cell mediated immune responses) however it goes back to 100% in the last month of pregnancy.
*Rubella infects the placenta via maternal viraemia which leads to necrotic areas in the chorionic villae epithelium <ref><pubmed>5949097</pubmed></ref>. It is thought that the rubella virus is passed through the fetal circulation via endothelial cell emboli. <ref><pubmed>2817948</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* It is an entirely preventable disease through the Rubella vaccine, being almost completely eliminated in western countries.

|- 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.
* Two 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 <ref><pubmed>3067168</pubmed></ref>
# 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''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 <ref name="PMID9161611"><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 greater amount of apoptosis during the inner ear development and thus decreased growth of neurons and myelin and subsequently the synapses. Intermittent conductive hearing loss is thought to be due to poorly formed eustachian tube <ref><pubmed>12795509</pubmed></ref>.
* The central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing <ref name="PMID9161611"/>.

|- 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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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 - Auditory Brainstem Response test]]

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===
[[File:Hearing_aids.JPG|thumb|200 px|right| 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 amplification 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 amplification 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 amplifier. The amplifier sends the impulses though the speaker into the ear as an increased sound.
<ref>National Institute of Health, '''Hearing Aid Basics''', http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx, Access date 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>6028666</pubmed></ref>

[[File:Cochlear_Implant.jpg|x250px|Cochlear Implant]]

==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

*'''Nonsyndromic deafness''': Hearing impairment not affiliated with other signs or symptoms

*'''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

*'''Syndromic deafness''': Hearing impairment occurring with additional abnormalities in the body

*'''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

== References ==
<references/>

==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]

{{External Links}}

==Image Gallery==

<gallery>

Image: Anatomy_of_the_Ear.JPG|thumb|left|350px|Anatomy of the ear
Image: Histology_of_Inner_Ear.png|thumb|right|300px|Histology of Inner Ear
Image: Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px|Pharyngeal arches one and two in mice embryo
Image: Devt_of_external_ear.JPG|thumb|400px|The image depicts the development of the pinna through the fetal development stages
Image: normal cochlea.png |thumb|150px|Wild-type inner ear showing normal morphology
Image: z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared
Image: otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo
Image: neural fate.jpg|thumb|200px|Recent model related to sensory fate.
Image: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle
Image: z3333865.gene expression.jpeg|thumb|300px|Representative expression patterns of genes controlling cochlear and vestibular specification.
Image: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea
Image: Dominant_diagram.jpg|x250px
Image: Autosomal_Recessive_Inheritance_Diagram.jpg|x250px
Image: X_Linked_Recessive_Diagram.jpg|x250px
Image: Pendred_Syndrome_Showing_Mondini_Defects.jpg|x450px
Image: MRI_of_Goldenhar_Syndrome.jpg
Image: Bilateral_Stenosis_of_Internal_Auditory_canal.jpg|x230px
Image: Enlarged_Vestibular_aqueduct.jpg|x250p
Image: Microtia_boy_surgery.jpg|x320px]
Image: Infant hearing test.jpg|thumb|300px|Testing the hearing of an infant - Auditory Brainstem Response test
Image: Cochlear_Implant.jpg|x250px|Cochlear Implant
Image: Atoh1 model.png|left|thumb|225px|Atoh1-cre is expressed in hair cells and causes transient limited expression of Atoh1 in CKO ears
Image: 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.

</gallery>

--[[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

2012-10-04T01:02:08Z

Z3292017: /* Environmental */

[[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'''|| The labyrinth of the ear is discovered. <ref name="PMID11314703"><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 name="PMID11314703"/> [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. <ref name="PMID16269359"><pubmed>16269359</pubmed></ref> <ref><pubmed>11237469</pubmed></ref>

[[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. <ref name="PMID16269359"/>

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. <ref name="PMID16269359"/> <ref><pubmed>21774850</pubmed></ref>

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==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px]]

The development of the outer and middle ear is attributed to the pharyngeal arches one and two. All the germ layer namely endoderm, mesoderm and ectoderm contribute to its formation. <ref><pubmed>8287791</pubmed></ref> The entire inner ear, as well as the neurons which innervate the sensory organ, are derived from the otic placode. <ref name="PMID17891709"><pubmed>17891709</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 and middle ear structures. 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. <ref><pubmed>11698185</pubmed></ref> 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.<ref name="PMID17891709"/> This will form an otic vesicle (otocyst) and further develop into the structures of the inner ear.

We will consider the outer, middle and inner ear separately.

===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 name="PMID10976045"><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 name="PMID10976045"/> <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.<ref name="PMID17891709"/>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"/>[[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>
[[File:z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared]]

'''2''' ''Pre-otic field''

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"/>
[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]

'''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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle]]

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'''
[[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>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them. <ref><pubmed>22778034</pubmed></ref>

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.<ref><pubmed>12530227</pubmed></ref> It exits through the internal acoustic meatus (IAM) to conduct signals to the brain for processing.

====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 name="PMID10980526"><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 name="PMID10980526"/>.
* 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>PMC3335728</pubmed></ref>.

|}

'''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
* Usher Syndrome predominantly affects the outer hair cells in the cochlear. Cochlear implants have given great improvements in both hearing and quality of life in these patients.
* 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 classic structural deformity is Mondini dysplasia of the cochlear whereby the cochlear is not complete having less than the required two and a half turns <ref><pubmed>3776519</pubmed></ref>.
* 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>.

||
[[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. It was also identified that 15 of the 23,000 pregnancies vertical transmission of the child contracting congenital toxoplasmosis <ref name="PMID3041362"><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* Detection of toxoplasmosis is achived through amniocentesis and subsequently using PCR to determine a positive result from DNA amplification <ref name="PMID3041362"/>.
* 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>. However inconclusive and inconsistent treatment investigations suggested to be caused by limited randomised controlled trials <ref><pubmed> 9988811 </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 <ref><pubmed>84910</pubmed></ref>.
* 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 <ref><pubmed>5949097</pubmed></ref>. 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 <ref><pubmed>2817948</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* 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.

|- 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 <ref><pubmed>3067168</pubmed></ref>
* 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''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 <ref name="PMID9161611"><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 <ref><pubmed>12795509</pubmed></ref>.
* Finally, the central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing <ref name="PMID9161611"/>.

|- 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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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 - Auditory Brainstem Response test]]

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===
[[File:Hearing_aids.JPG|thumb|200 px|right| 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 amplification 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 amplification 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 amplifier. The amplifier sends the impulses though the speaker into the ear as an increased sound.
<ref>National Institute of Health, '''Hearing Aid Basics''', http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx, Access date 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>6028666</pubmed></ref>

[[File:Cochlear_Implant.jpg|x250px|Cochlear Implant]]

==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

*'''Nonsyndromic deafness''': Hearing impairment not affiliated with other signs or symptoms

*'''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

*'''Syndromic deafness''': Hearing impairment occurring with additional abnormalities in the body

*'''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

== References ==
<references/>

==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]

{{External Links}}

==Image Gallery==

<gallery>

Image: Anatomy_of_the_Ear.JPG|thumb|left|350px|Anatomy of the ear
Image: Histology_of_Inner_Ear.png|thumb|right|300px|Histology of Inner Ear
Image: Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px|Pharyngeal arches one and two in mice embryo
Image: Devt_of_external_ear.JPG|thumb|400px|The image depicts the development of the pinna through the fetal development stages
Image: normal cochlea.png |thumb|150px|Wild-type inner ear showing normal morphology
Image: z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared
Image: otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo
Image: neural fate.jpg|thumb|200px|Recent model related to sensory fate.
Image: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle
Image: z3333865.gene expression.jpeg|thumb|300px|Representative expression patterns of genes controlling cochlear and vestibular specification.
Image: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea
Image: Dominant_diagram.jpg|x250px
Image: Autosomal_Recessive_Inheritance_Diagram.jpg|x250px
Image: X_Linked_Recessive_Diagram.jpg|x250px
Image: Pendred_Syndrome_Showing_Mondini_Defects.jpg|x450px
Image: MRI_of_Goldenhar_Syndrome.jpg
Image: Bilateral_Stenosis_of_Internal_Auditory_canal.jpg|x230px
Image: Enlarged_Vestibular_aqueduct.jpg|x250p
Image: Microtia_boy_surgery.jpg|x320px]
Image: Infant hearing test.jpg|thumb|300px|Testing the hearing of an infant - Auditory Brainstem Response test
Image: Cochlear_Implant.jpg|x250px|Cochlear Implant
Image: Atoh1 model.png|left|thumb|225px|Atoh1-cre is expressed in hair cells and causes transient limited expression of Atoh1 in CKO ears
Image: 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.

</gallery>

--[[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

2012-10-04T00:51:00Z

Z3292017: /* Genetic */

[[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'''|| The labyrinth of the ear is discovered. <ref name="PMID11314703"><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 name="PMID11314703"/> [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. <ref name="PMID16269359"><pubmed>16269359</pubmed></ref> <ref><pubmed>11237469</pubmed></ref>

[[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. <ref name="PMID16269359"/>

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. <ref name="PMID16269359"/> <ref><pubmed>21774850</pubmed></ref>

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==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px]]

The development of the outer and middle ear is attributed to the pharyngeal arches one and two. All the germ layer namely endoderm, mesoderm and ectoderm contribute to its formation. <ref><pubmed>8287791</pubmed></ref> The entire inner ear, as well as the neurons which innervate the sensory organ, are derived from the otic placode. <ref name="PMID17891709"><pubmed>17891709</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 and middle ear structures. 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. <ref><pubmed>11698185</pubmed></ref> 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.<ref name="PMID17891709"/> This will form an otic vesicle (otocyst) and further develop into the structures of the inner ear.

We will consider the outer, middle and inner ear separately.

===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 name="PMID10976045"><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 name="PMID10976045"/> <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.<ref name="PMID17891709"/>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"/>[[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>
[[File:z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared]]

'''2''' ''Pre-otic field''

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"/>
[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]

'''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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle]]

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'''
[[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>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them. <ref><pubmed>22778034</pubmed></ref>

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.<ref><pubmed>12530227</pubmed></ref> It exits through the internal acoustic meatus (IAM) to conduct signals to the brain for processing.

====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 name="PMID10980526"><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 name="PMID10980526"/>.
* 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>PMC3335728</pubmed></ref>.

|}

'''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
* Usher Syndrome predominantly affects the outer hair cells in the cochlear. Cochlear implants have given great improvements in both hearing and quality of life in these patients.
* 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 classic structural deformity is Mondini dysplasia of the cochlear whereby the cochlear is not complete having less than the required two and a half turns <ref><pubmed>3776519</pubmed></ref>.
* 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>.

||
[[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 <ref name="PMID3041362"><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* Detection of toxoplasmosis is achived through amniocentesis and subsequently using PCR to determine a positive result from DNA amplification <ref name="PMID3041362"/>.
* 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 <ref><pubmed>84910</pubmed></ref>.
* 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 <ref><pubmed>5949097</pubmed></ref>. 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 <ref><pubmed>2817948</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* 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.

|- 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 <ref><pubmed>3067168</pubmed></ref>
* 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''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 <ref name="PMID9161611"><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 <ref><pubmed>12795509</pubmed></ref>.
* Finally, the central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing <ref name="PMID9161611"/>.

|- 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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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 - Auditory Brainstem Response test]]

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===
[[File:Hearing_aids.JPG|thumb|200 px|right| 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 amplification 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 amplification 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 amplifier. The amplifier sends the impulses though the speaker into the ear as an increased sound.
<ref>National Institute of Health, '''Hearing Aid Basics''', http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx, Access date 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>6028666</pubmed></ref>

[[File:Cochlear_Implant.jpg|x250px|Cochlear Implant]]

==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

*'''Nonsyndromic deafness''': Hearing impairment not affiliated with other signs or symptoms

*'''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

*'''Syndromic deafness''': Hearing impairment occurring with additional abnormalities in the body

*'''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

== References ==
<references/>

==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]

{{External Links}}

==Image Gallery==

<gallery>

Image: Anatomy_of_the_Ear.JPG|thumb|left|350px|Anatomy of the ear
Image: Histology_of_Inner_Ear.png|thumb|right|300px|Histology of Inner Ear
Image: Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px|Pharyngeal arches one and two in mice embryo
Image: Devt_of_external_ear.JPG|thumb|400px|The image depicts the development of the pinna through the fetal development stages
Image: normal cochlea.png |thumb|150px|Wild-type inner ear showing normal morphology
Image: z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared
Image: otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo
Image: neural fate.jpg|thumb|200px|Recent model related to sensory fate.
Image: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle
Image: z3333865.gene expression.jpeg|thumb|300px|Representative expression patterns of genes controlling cochlear and vestibular specification.
Image: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea
Image: Dominant_diagram.jpg|x250px
Image: Autosomal_Recessive_Inheritance_Diagram.jpg|x250px
Image: X_Linked_Recessive_Diagram.jpg|x250px
Image: Pendred_Syndrome_Showing_Mondini_Defects.jpg|x450px
Image: MRI_of_Goldenhar_Syndrome.jpg
Image: Bilateral_Stenosis_of_Internal_Auditory_canal.jpg|x230px
Image: Enlarged_Vestibular_aqueduct.jpg|x250p
Image: Microtia_boy_surgery.jpg|x320px]
Image: Infant hearing test.jpg|thumb|300px|Testing the hearing of an infant - Auditory Brainstem Response test
Image: Cochlear_Implant.jpg|x250px|Cochlear Implant
Image: Atoh1 model.png|left|thumb|225px|Atoh1-cre is expressed in hair cells and causes transient limited expression of Atoh1 in CKO ears
Image: 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.

</gallery>

--[[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

2012-10-04T00:40:24Z

Z3292017: /* Genetic */

[[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'''|| The labyrinth of the ear is discovered. <ref name="PMID11314703"><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 name="PMID11314703"/> [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. <ref name="PMID16269359"><pubmed>16269359</pubmed></ref> <ref><pubmed>11237469</pubmed></ref>

[[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. <ref name="PMID16269359"/>

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. <ref name="PMID16269359"/> <ref><pubmed>21774850</pubmed></ref>

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==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px]]

The development of the outer and middle ear is attributed to the pharyngeal arches one and two. All the germ layer namely endoderm, mesoderm and ectoderm contribute to its formation. <ref><pubmed>8287791</pubmed></ref> The entire inner ear, as well as the neurons which innervate the sensory organ, are derived from the otic placode. <ref name="PMID17891709"><pubmed>17891709</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 and middle ear structures. 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. <ref><pubmed>11698185</pubmed></ref> 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.<ref name="PMID17891709"/> This will form an otic vesicle (otocyst) and further develop into the structures of the inner ear.

We will consider the outer, middle and inner ear separately.

===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 name="PMID10976045"><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 name="PMID10976045"/> <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.<ref name="PMID17891709"/>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"/>[[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>
[[File:z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared]]

'''2''' ''Pre-otic field''

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"/>
[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]

'''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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle]]

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'''
[[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>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them. <ref><pubmed>22778034</pubmed></ref>

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.<ref><pubmed>12530227</pubmed></ref> It exits through the internal acoustic meatus (IAM) to conduct signals to the brain for processing.

====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 name="PMID10980526"><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 name="PMID10980526"/>.
* 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>PMC3335728</pubmed></ref>.

|}

'''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
* Usher Syndrome predominantly affects the outer hair cells in the cochlear. Cochlear implants have given great improvements in both hearing and quality of life in these patients.
* 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 <ref name="PMID3041362"><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* Detection of toxoplasmosis is achived through amniocentesis and subsequently using PCR to determine a positive result from DNA amplification <ref name="PMID3041362"/>.
* 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 <ref><pubmed>84910</pubmed></ref>.
* 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 <ref><pubmed>5949097</pubmed></ref>. 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 <ref><pubmed>2817948</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* 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.

|- 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 <ref><pubmed>3067168</pubmed></ref>
* 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''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 <ref name="PMID9161611"><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 <ref><pubmed>12795509</pubmed></ref>.
* Finally, the central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing <ref name="PMID9161611"/>.

|- 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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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 - Auditory Brainstem Response test]]

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===
[[File:Hearing_aids.JPG|thumb|200 px|right| 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 amplification 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 amplification 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 amplifier. The amplifier sends the impulses though the speaker into the ear as an increased sound.
<ref>National Institute of Health, '''Hearing Aid Basics''', http://www.nidcd.nih.gov/health/hearing/pages/hearingaid.aspx, Access date 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>6028666</pubmed></ref>

[[File:Cochlear_Implant.jpg|x250px|Cochlear Implant]]

==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

*'''Nonsyndromic deafness''': Hearing impairment not affiliated with other signs or symptoms

*'''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

*'''Syndromic deafness''': Hearing impairment occurring with additional abnormalities in the body

*'''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

== References ==
<references/>

==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]

{{External Links}}

==Image Gallery==

<gallery>

Image: Anatomy_of_the_Ear.JPG|thumb|left|350px|Anatomy of the ear
Image: Histology_of_Inner_Ear.png|thumb|right|300px|Histology of Inner Ear
Image: Pharyngeal_arch_one_and_two_in_mice.png|thumb|200px|Pharyngeal arches one and two in mice embryo
Image: Devt_of_external_ear.JPG|thumb|400px|The image depicts the development of the pinna through the fetal development stages
Image: normal cochlea.png |thumb|150px|Wild-type inner ear showing normal morphology
Image: z3333865.pax2 and 8.jpg|thumb|200px|Early expression of Pax2 and Pax8 compared
Image: otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo
Image: neural fate.jpg|thumb|200px|Recent model related to sensory fate.
Image: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle
Image: z3333865.gene expression.jpeg|thumb|300px|Representative expression patterns of genes controlling cochlear and vestibular specification.
Image: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea
Image: Dominant_diagram.jpg|x250px
Image: Autosomal_Recessive_Inheritance_Diagram.jpg|x250px
Image: X_Linked_Recessive_Diagram.jpg|x250px
Image: Pendred_Syndrome_Showing_Mondini_Defects.jpg|x450px
Image: MRI_of_Goldenhar_Syndrome.jpg
Image: Bilateral_Stenosis_of_Internal_Auditory_canal.jpg|x230px
Image: Enlarged_Vestibular_aqueduct.jpg|x250p
Image: Microtia_boy_surgery.jpg|x320px]
Image: Infant hearing test.jpg|thumb|300px|Testing the hearing of an infant - Auditory Brainstem Response test
Image: Cochlear_Implant.jpg|x250px|Cochlear Implant
Image: Atoh1 model.png|left|thumb|225px|Atoh1-cre is expressed in hair cells and causes transient limited expression of Atoh1 in CKO ears
Image: 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.

</gallery>

--[[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}}

User:Z3292017

2012-10-03T02:07:11Z

Z3292017: /* Lab Attendance */

=='''Lab Attendance'''==

Lab 1 - [[User:Z3292017|Z3292017]] 10:15, 25 July 2012 (EST)

Lab 2 - [[User:Z3292017|Z3292017]] 10:17, 1 July 2012 (EST)

Lab 3 - [[User:Z3292017|Z3292017]] 10:13, 8 August 2012 (EST)

Lab 4 - [[User:Z3292017|Z3292017]] 11:23, 15 August 2012 (EST)

Lab 5 - [[User:Z3292017|Z3292017]] 10:34, 22 August 2012 (EST)

Lab 6 - [[User:Z3292017|Z3292017]] 11:31, 29 August 2012 (EST)

Lab 7 - [[User:Z3292017|Z3292017]] 10:14, 12 September 2012 (EST)

Lab 8 - [[User:Z3292017|Z3292017]] 10:13, 19 September 2012 (EST)

Lab 9 - [[User:Z3292017|Z3292017]] 11:11, 26 September 2012 (EST)

Lab 10 - [[User:Z3292017|Z3292017]] 11:06, 3 October 2012 (EST)

==Lab 1 - [[User:Z3292017|Z3292017]]==

'''Lab 1 Online Assessment'''

''Question 1: Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique:''

The origin of IVF can be dated from the late 19th Century where embryo transplantation in rabbits was discovered by Walter Heape. The development of IVF was due to a cascade of events during the 20th century. Pincus and Enzmann from Harvard University suggested the possibility that mammalian eggs are able to develop normally in vitro in 1934. In 1948 Menken and Rock exposed 138 oocytes to spermatozoa in vitro. In 1959, Change was able to provide evidence for IVF by fertilising rabbit eggs with capicated sperm and thus achieve birth. From 1965 Robert Edwards attempted to fertilise human oocytes in vitro. In 1968 Edwards successfully fertilised a human egg using a human culture media he developed. Finally after years of research and failed attempts, the first test tube baby was born in 1978.
Robert Edwards was awarded the Nobel Prize in Physiology and Medicine in 2010 due to his immense development and contribution of IVF.

'''References'''
<references/>
#http://www.ivf-worldwide.com/ivf-history.html
#http://en.wikipedia.org/wiki/In_vitro_fertilisation
#http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/

''Question 2: Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings:''

Cleavage speed and implantation potential of early cleavage embryos in IVF or ICSI cycles by Lee, Lin and Hwu (July, 2012) attempted to determine the correlation of early embryo cleavage, its speed and the potential implantation rates for IVF. Their definition of early cleavage was embryonic mitosis occurring 25-27 hours after insemination. The embryos’ (day 3) cleavage speed was assessed and rated into 3 groups: rapid (more than 9 cells), normal (7-8 cells) and slow (less than 7 cells) along with their morphological quality being either good or poor. Normal fertilisation was determined by the presence of 2 nuclei and 2 polar bodies. 25-27 hours after IVF an early cleavage examination took place to determine which embryos had already cleaved. They embryos were then examined for their quality from 66-68 hours after IVF.

Early cleavage emrbyos developed normally in comparison to non early cleavage embryos. Notably, the early cleavage embryos produced a greater amount of “good quality” embryos and subsequently the implantation rate was sufficiently greater with early cleavage embryos. This finding is of great importance as embryo morphology is the most important tool to select the best embryo to transfer andthus increase the rates of implantation, pregnancy and live birth.

'''References'''

Lee MJ, Lee RK, Lin MH, Hwu YM '''Cleavage speed and implantation potential of early-cleavage embryos in IVF or ICSI cycles.''' J Assist Reprod Genet. 2012 Jul 25 PMID: 22825967

==Lab 2 - [[User:Z3292017|Z3292017]]==

'''Lab 2 Online Assessment'''

''Question 1: Image from journal source''

[[File:zygote.jpg]]

Zygotes showing different distribution of NPB in the 2PN and different PB alignment <ref>Alessia Nicoli, Francesco Capodanno, Lucia Moscato, Ilaria Rondini, Maria T Villani, Antonella Tuzio, and Giovanni B La Sala (2010) '''Analysis of pronuclear zygote configurations in 459 clinical pregnancies obtained with assisted reproductive technique procedures''' Department of Obstetrics and Gynecology, Arcispedale Santa Maria Nuova, Reprod Biol Endocrinol. 2010; 8: 77. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902489/?tool=pubmed NCBI]</ref>

===Reference===

<references/>

''Question 2: Identify a protein associated with the implantation process, including a brief description of the protein's role''

Proprotein convertase 6 (PC6) is a necessary regulatory molecule for embryo implantation which generates bioactive proteins such as growth factors, peptide hormones and adhesion molecules. It is produced in the uterine stromal cells in particular at the embryo attachment site throughout early pregnancy in mice. In order for implantation to occur, the uterus ungergoes morphological and physiological changes, one being differentiation of endometrial stromal cells.

Studies have shown that PC6 mRNA is upregulated in particularly at the site of embryo attachment in the mouse uterus, being predominantly at the antimesometrial pole undergoing decidualisation. These results imply that PC6 is associated with decidualisation. From this study, the researchers were able to determine that endometrial PC6 is imperative for maternal stromal decidual response for an implanting embryo during the time of implantation. They discovered that endometrial PC6 is produced explicitly in decidual cells (the vascular and cellular changes in a uterus in preparation for pregnancy) and is not found in other cells as well as the embryo. Similarly, they noted that inhibition of the production of PC6 early on (around day 3.5) using anti-PC6 MO blocked the decidualisation and thus impeded implantation. Notably, PC6 is produced in the late secretory phase of the menstrual cycle in preparation for implantation.

===Reference===

Guiying Nie, Ying Li, Min Wang, Yi Xun Liu, Jock K. Findlay and Lois A. Salamonsen '''Inhibiting Uterine PC6 Blocks Embryo Implantation: An Obligatory Role for a Proprotein Convertase in Fertility''' Biology of Reproduction April 1, 2005 vol. 72 no. 4 1029-1036. [http://www.biolreprod.org/content/72/4/1029.long Biology of Reproduction]

==Lab 3 - [[User:Z3292017|Z3292017]]==

'''Lab 3 Online Assessment'''

''Question 1: Difference between post fertilisation age and gestational age''

Post fertilisation age (embryonic age) is dated at fertilisation of the egg which is approximately 2 weeks after the gestational age. This however is far less easy to determine than the gestational age as they calculate the time of ovulation as the oocyte is normally fertilised within the 12 hour period after ovulation.

Gestational age is the date of the beginning of the last normal menstrual period and is clinically more commonly used as it is a much easier method to calculate. Notably, the crown-rump length of the fetus along with the head and femur length are later used to confirm the estimated age of the fetus.

[http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00005-9--s0050&isbn=978-1-4377-2002-0&uniqId=351438666-2#4-u1.0-B978-1-4377-2002-0..00005-9--s0075| Estimation of gestational and embryonic age]

''Question 2: 3 different types of tissues formed from somites''

Ventromedially, the somite differentiates into the sclerotome which forms the vertebrae and the ribs. Studies have shown that Pax-1 is essential for the ventral sclerotome differentiation. The sclerotome differentiates into the vertebrae and ribs through bone formation. [http://www.ncbi.nlm.nih.gov/pubmed/8026324 Role of Pax-1 in skeleton development]. This is primarily initiated with mesenchymal cells which assists the formation of the pre-cartilage mass via chrondrocytes and subsequently cartilage formation. Bone then develops through the replacement of cartilaginous tissue with bone tissue. [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00014-X&isbn=978-1-4377-2002-0&uniqId=351438666-4 Development of bone and cartilage]

Dorsolaterally, the somite first differentiates into the dermomyotome which then creates 2 regions. The myotome region forms primordial muscle cells (myoblasts) and the dermatome region forms the fibroblasts (dermis). [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00015-1&isbn=978-1-4377-2002-0&uniqId=351438666-4#4-u1.0-B978-1-4377-2002-0..00015-1 Development of Muscle]

Dermatome along with Neurotrophin-3 assists with the early formation of the dermis. [http://www.ncbi.nlm.nih.gov/pubmed/7671821 Role of Neurotrophin-3] The dermal papillae consist mainly of fibroblasts and is located close to the epidermis. It contains both elastin and collagen fibres (produced by fibroblasts) with the elastin fibres perpendicular to the surface of the skin. The reticular dermis accounts for the majority of the dermis with multidirectional elastin and collagen fibres. Notably, in the dermal papillae, a plexus consisting of numerous blood vessels are found but do not penetrate into the epidermis. Some nerves within this region do penetrate through to the epidermis via free nerve endings which are linked to nerve corpuscles, such as Meissner's plexus. [http://www.skin-science.com/_int/_en/topic/topic_sousrub.aspx?tc=SKIN_SCIENCE_ROOT%5EAN_ORGAN_REVEALED%5ETHE_DERMIS&cur=THE_DERMIS Dermis formation]

Myotomes are separated into [http://embryology.med.unsw.edu.au/embryology/index.php?title=Musculoskeletal_System_-_Muscle_Development#Myotome epaxial muscles and hypaxial muscles] via primordial muscle cells . The epaxial muscles form the skeletal muscles dorsal to the vertebral column known as the erector spinae muscles. The hypaxial muscles form the ventral skeletal muscles which contribute to the lung and limb formation. The skeletal muscle fiber is long, cylindrical and multinucleated, with peripherally located nuclei.

==Lab 4 - [[User:Z3292017|Z3292017]]==

'''Lab 4 Online Assessment'''

''Question 1: 2 invasive prenatal diagnostic techniques related to the placenta:''

1. Amniocentesis:

A relatively common yet invasive procedure normally conducted between weeks 15-18 of gestation. A 22 gauge needle is inserted through the anterior abdominal and uterine walls (around the region of the umbilicus) of the mother into the amniotic cavity. Of the approximate 200mL volume that the mother is carrying at this early stage of pregnancy, only 15-20mL can be withdrawn safely. There is usually little risk when performing this procedure as an ultrasonography can be used concurrently to outline the fetal and placental position.

Amniocentesis is a procedure used to determine many genetic disorders such as Down Syndrome and also neural tube defects such as spina bifida cystica. [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00006-0--s0100&isbn=978-1-4377-2002-0&uniqId=352651422-2#4-u1.0-B978-1-4377-2002-0..00006-0--s0110| Amniocentesis - The Developing Human]

2. Chorionic Villus Sampling:

Trophoblastic tissue biopsies between 5-20 mg can be obtained through inserting a needle through the abdominal and uterine walls of the mother into the uterine cavity. This can also be completed transcervically using a polyethylene catheter through the cervix to obtain a chorionic villus sample. There is a slightly greater risk of miscarriage after this procedure has been performed when compared to amniocentesis (of around 1%).

Chorionic villus sampling is a procedure used to detect chromosomal abnormalities and also X linked disorders. The benefit of CVS over amniocentesis is that it can be performed between the 10th-12th week of gestation and thus giving an earlier diagnosis. [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00006-0--s0100&isbn=978-1-4377-2002-0&uniqId=352651422-2#4-u1.0-B978-1-4377-2002-0..00006-0--s0125| Chorionic Villus Sampling - The Developing Human]

''Question 2: Paper using cord stem cell therapeutically discussion of findings:''

Lim JY, Jeong CH, Jun JA, Kim SM, Ryu CH, Hou Y, Oh W, Chang JW, Jeun SS '''Therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of cerebral ischemia''' Stem Cell Res Ther. 2011; 2(5): 38 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3308035/?tool=pubmed| PMID: 21939558]

In this paper, the researchers investigated the effects of therapeutic potential of mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of stroke. Following this, the researchers then investigated whether the mesenchymal stem cells could enter and survive in the brain, and their potential to improve post stroke functional recovery. Mesenchymal stem cells (MSC) are a promising therapeutic strategy for the treatment of stroke due to their high proliferative capacity and also that they can be easily obtained.

The mesenchymal stem cells were injected intrathecally in some rats and intravenously in the others three days after Middle Coronary Artery Occlusion (MCAO) using isoflurane anesthesia. A 1cm incision was made over L3-L5 spinous processes and a neonatal lumbar puncture needed (25 gauge) was inserted into the spinal canal. MSCs (1 × 10^6) was diluted with 20 μl PBS being injected into the CSF over 30 seconds. Intravenously, MSCs (1 × 10^6) was diluted with 700 μl PBS were injected slowly for five minutes via an intravenous cannula situated in the tail vein. The presence and survival of the MSCs in the brain tissue was examined by immunohistochemistry. The rats were examined by their recovery of coordination of movement using both the Rotarod test and the adhesive removal test after the 1st, 2nd, 3rd and 4th week of stroke.

The results indicated that the MSC intrathecally receiving rats had an increased level of migrated cells to the ischemic area compared to the intravenous administration of MSCs. Additionally, many of the cells were expressing the mature neural lineage markers. Overall, the intrathecal administration of MSCs were more effective in reducing ischemic damage, yet proved to be similar to intravenous administration in promoting neurological recovery.

This study thus indicated a potential treatment for cerebral ischemia or neurodengerative disorders due to its ability to recover ischemic damaged tissue.

== Lab 7 ==

'''Lab 7 Online Assessment'''

''Question 1''

''(a) Definition of muscle satellite cell''

A muscle satellite cell is a quiescent mononucleated cell, which respond to injury by proliferating to form regenerated muscle and additional satellite cells, found between the basement membrane of specialised muscle fibres. [http://www.ncbi.nlm.nih.gov/pubmed/12757751| Muscle Satellite Cell PMID: 12757751]

''(b) Two examples of when satellite cells are activated''

Satellite cells are employed for skeletal muscle trauma and also disease.

* Muscle injury: When muscle injury occurs, the satellite cells are activated and will either form multinucleated myotubes to assist with muscle regeneration, or will form additional quiescent satellite cells in order to assist with more [http://www.ncbi.nlm.nih.gov/pubmed?term=The%20muscle%20satellite%20cell%20at%2050%3A%20the%20formative%20years| muscle regeneration]. Sambasivan et al. indicated in their 1993 study that other cells with regenerative potential depend on the satellite cell presence especially the Pax7 expressing satellite cells. [http://dev.biologists.org.wwwproxy0.library.unsw.edu.au/content/138/17/3647| Pax7-expressing satellite cells]

* Muscle disease: Research has shown that congenital myopathies such as Duchenne Muscular Dystrophy lead to a greater number of satellite cells than in normal muscle cells. Notably, the regenerative capacity of, for example Duchenne Muscular Dystrophy, is limited due to the severity and continuation of the disease. [http://genesdev.cshlp.org.wwwproxy0.library.unsw.edu.au/content/20/13/1692| Muscle stem cells in development, regeneration, and disease]

''Question 2: 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''

Spinal cord injury will result in partial or complete paralysis of the muscle innervation at or below the trauma level of the spinal cord resulting in atrophy. Some studies have noted that a some paralysed muscles due to spinal cord injury have an increase in force per cross sectional area of the muscle compared to normal in an attempt to maintains the muscle's normal strength. However, it is also important to note, the muscle cross sectional area significantly decreased. Due to the decrease in muscle, the study also indicated that there were increased levels of connective tissues and fat - thought to transfer more of the force to the tendon. Importantly, in chronic muscle denervation (greater than 50% of muscle size loss), the strength of the muscle (if there was any at all) has seriously deteriorated. [http://www.ibib.waw.pl/bbe/bbefulltext/bbe_25_3_039_ft.pdf| Muscle Atrophy after Human Spinal Cord Injury]

After a spinal cord injury the muscle fibre type pattern changes from a mix of type I and type II to predominantly type II fast glycolytic fibres. This is thought be an explanation of the quick muscle fatigue noted in rehabilitation. Notably, Burnham et al. discovered that the muscle fibre type change occurs in stages rather than an immediate effect and thus opens the door to more research to prevent the transformation of the muscle types from occurring, which is inidcated to be done within the first week or two following spinal cord injury. [http://www.ncbi.nlm.nih.gov/pubmed/9044514| Skeletal muscle fibre type transformation following spinal cord injury]

==Lab 8==

'''Lab 8 Online Assessment'''

'''Vision'''

The photo at the top of your page is a great choice and makes the site that much more appealing. The only suggestion I would have here is to potentially minimise the photo as it makes the contents section to the left of it hard to read. Your introduction is clear and concise and gives a good description of the eye. A slight adjustment I would make is perhaps to make it slightly longer giving a brief discussion about what is to be discussed on this page. Included in your introduction you have the anatomy of the eye. Firstly, would it be appropriate to include the histology as well, as it appears further down the page you discuss the cells, so perhaps if you gave a brief histological overview that could make the sections below easier for the reader to comprehend. I would probably add to that that if you were to include histology, to put the anatomy and histology into a new section just so it doesn’t clutter the introduction.

Your history, although I’m aware it ins’t finished, would read better if it were in a table and would also bring some more colour to the page. I’m assuming this will come when you finish this section, but it would be wise to include updated examples as well in order to show an adequate progression of the history.

The development section appears to be very thorough which is fantastic. It is rather clear that you have put a lot of research and time into this section. The introduction you have there is well written and again concise which is great. Additionally I like your use of photos just below it to further your explanation and also to break up the text. In regards to your photos, I would suggest perhaps a better description of them and to make sure you include where you got the photo from. If there were an explanation of the photo in simplistic terms, then I think the photos would be really beneficial.

The optic nerve section is well written but it appears to lack references?? In the first 3 paragraphs there are only 2 references. I would probably suggest that this information is backed up by additional sources as well. Also, with your hand drawn pictures (which are good), I would suggest an explanation on them when you open the picture up in another window. Your paragraph describing the 2 pictures, I would probably recommend that it become sintegrated within the text i.e. when you are talking about that part of it then include it there. I just think it would make it flow better that way – like you have done with figure 3.

The retina is good and well set out with pictures. However I noticed that you have used the exact references as before (3, 4)?? It would be really advisable to include many more references than what is listed. The same applies to the images as I said above, but good integration!

The ciliary body appears to be well researched and referenced. From the iris down there appears to be a lack of new references and also looks rather bland - so here I would suggest including additional photos from journal articles you have used. Also, it seems rather brief, I’m wondering whether there is more information about the embryological processes that could be included?

The current research is a good start, but there isn’t much of an explanation of the photo that is included and brief discussion of the research should probably be included. Are there additional research projects to include as well?

Finally, your references ar good but short. The fisrt 2 need to be put in the appropriate format. I would definitely suggest including many more references in order to make your information listed more valid.

'''Somatosensory development'''

I really like your introduction, I think that is is really informative and gives the reader a much clearer understanding of what this topic is about. Your references here need to be included in the reference section below but it appears that you have a good amount of references for the points depicted. At the end of the first paragraph it discusses a picture of the general organisation however there is not one there?? Also the inclusion of a picture would be agreat idea not only to further our understanding but also to break up the text and make it more appealing.

In your history of discoveries section I would probably recommend putting this in a colourful table, again to rbeak up the text, and also to make it easier to read. I would probably suggest here that you include a greater progression of discoveries to show the change of thinking over time. Note to also inlduce the appropriate referencing as shown in previous lab classes.

The central somatosensory differentiation is very expansive and informative. I would assume that you have put a lot of research into this section. Note that you have used pretty well the same references over and over. I would suggest that you include additional references to back up those statements as well. If those couple of references were the only ones saying that information, then I would suggest further researching to ensure that other journal articles don’t contradict this. The image is good and appears to show a good somatosensory pathway, however I would make the font bigger, so that it would not be imperative to enlarge the photo to read what is there. The picture has a discription when it is enlarged which is good, but I think it would also be appropriate to put the correct student information for the referencing.

In the Touch part, I noted that almost none of the text is refenced, which essentially makes the information listen invalid, so I would look into finding appropriate references here. Also, this section seems a bit dull with no pictures. Perhaps histological photos could be included here? I know we studied them in histology and this would make the section more interesting and also compliment the information stated. I would also suggest that those subheadings you don’t want in bold, you list in italic with two ‘ ‘ in order to separate it from the text below..

The Pain section probably needs to be set out better by using dot points? It appears that you have provided some excellent information but it is also important to put the references included with the reference section below. A photo here might be nice, perhaps of the different fibres if this can be found?

The Hot/Cold section is better set out and I like the appropriate referencing here. However, it appears that you are re-using the same references, so I would suggest some more research be done here to compliment your other references. It is better set out, however I would suggest some photos to be included if at all appropriate and can be found.

Pressure is similar to the pain section in the sense that the references really need to be put in the referencing section. It would also be advisable that you split the first paragraph up as it is rather long and not very appealing for one to read.

Current research section is good and concise. I like the use of the picture there, and I like the description that you have when you enlarge the picture. Is there any other current research happening now?

Finally, I would suggest adding more information outlining the development of these areas as I believe this to have been limited across the majority of sections. Although you are providing good reaseach and information describing these sections, as this is am embryology course, I would see it as appropriate that some sort of developmental progression is included – or if this is not known as of yet, for that to be stated. I would also highly recommend that you include a detailed glossary of words, as this is rather incomplete.

'''Taste development'''

The introduction section is very informative and I like the picture included discussing the 5 basic tastes which is interesting to read. I really enjoy your descriptions of bitter and sweet and find it interesting to read. I like the research you included in this section but I believe this needs to be referenced. Currently in the introduction you have only 1 references, so I would suggest that you find more to further validate your information (note that there are no references in the first paragraph). I like in your picture that you included a description. The cell biology section I would probably put in its own section with = = to break up the contend displayed. In this section it is clear that this has been researched however there have been no references listed at all here.

The taste map section has clearly been well researched yet poorly referenced. It would be interesting to look at if possible a progression of the understanding of the taste map. In the picture of the tongue, I would suggest that it has a better description on the enlarged image. However, some of this text is rather hard to read, such as the descriptions of the first and second order neurons. As you have included terms in there which would be foreign to most people, I would try to include either a picture to show exactly where these parts are such as the NTS which can give the reader a better understanding of what you’re saying. Note that you say things like “copious scientific conjecture surrounds…” however there is no references here! This section is well researched which is great, but I would really consider putting it into slightly easier terms to better comprehension.

In the cortical areas section, a similar approach applies: when describing locations of things such as the I/fO, you should really include a clear diagram as to where all of these are. I can see you included the section of the brain however don’t see it as too informative so a better description there would be appropriate. I would also note that you are repeating your references again, and it would be advisable that you find alternative information to include as well.

The timeline section is very informative and really stands out. I’m assuming you will be including the photos later this week. This is well written and gives a truly informative description of the embryological changes that occur. It will look much better and be better to understand once the photos have been included. Note that you have used the same references pretty well the whole time in this section. Although that paper may have a lot of information about what you are needing to talk about, I would also encourage you to research more papers in order to compliment the information you have listed.

The history of discoveries section is well set out and clear and concise. In some areas I would suggest a brief descripton of what you have written such as “PKD2L”, and also make sure you include the appropriate references as all I can see currently it numbers.

In the adult tongue and taste bud section, is this also what the tongue looks like from week 15? If not what changes occurs for it to form into what you have described as the adult tongue and what enhances these changes? This section is informative however it is really lacking references. The taste bud picture you have is quite good, but is that also what the taste bud looks like at 15 weeks?

The abnormalities section is really interesting and is rather enjoyable to read. Are they the only abnormalities that can happen to the tongue? How about environmental? Does alcohol, smoking or drugs affects its development of either the tongue or the taste buds? Additonally, your current research is very thorough and interesting. In regards to the photos you have there, I would make sure that they are set out appropriately, with the information that this is a student project.

Finally, the glossary needs to be highlighted to make it stand out and more words need to be included. Note that in your references, reference 5 can not be accessible, so make sure you fix that up. Overall, it was interesting to read and I enjoyed the display of photos that were also included!

'''Olfaction'''

Your introduction is good and concise giving a simple understanding of the olfactory system. Here I would suggest that you include what you’re about to discuss on the page. I also think you should include some references and maybe a photo in this section. The references to show that this information has been researched and the photo to break up the text and give the reader a simple understanding of the olfactory system.

The history of discovery section is clearly well researched and is well set out. However, I would suggest that you include brief descriptions of what has been described such as the Vomeronasal organ or the Nobel Prize which will further enhance the readers understanding. You have a good use of references there as well. In the picture that was included in this section, I would provide a more indepth description of what is drawn i.e. what the ectoderm is etc.

The timeline of developmental process is really well set out and easy to read. I would just make sure that every new point you include, you put it with a references as some of your points are not referenced at all and you need to be careful of that! I would also suggest that you put it in appropriate bullet points using the star key on your keyboard, that way it can be set out a bit better. Also, at the end of week 8, does this mean the olfactory system is complete by then? If so, then I would suggest you state that in that final week, if not, then what other small changes occur throughout the duration of the pregnancy? Also note that week 6 – 8 the references are either limited or not there, so I would recommend putting them in.

The anatomy of the olfactory system and the normal function are limited in information but also have only one reference between them. The images attached should really have more of a description when the picture is enlarged to give the reader a better understanding of what you’re talking about. Such as: diagram of olfactory bulb- what does it do and where is it located?

The abnormality section is rather indepth for 2 conditions, are there any other factors that come into play in regards to olfactory defects? Such as environmental? The Kallmann’s syndrome is really indepth and describes the clinical features, diagnosis and treatment, could this also be implementd with the Choanal atresia? Or are the same techniques used there? Also, be careful when you use shortening of words such as OB, you provided the HH in brackets first, so I would suggest the same is done with the olfactory bulb just to prevent confusion. I like your use of both images and give s a simple but good explanation of what you have been discussing (and also breaks up the text!). I like how you have provided a good description in the enlarged picture and it makes it easier for the reader to understand.

The current research section really shows that you have put a lot of effort in for this section. However, at the beginning of each new research you state either a study or a paper with a link, perhaps use the name of the paper and who wrote it and use that as the link instead. It is really interesting and I rather enjoyed reading it, however, if possible I would add some more photos just to break up the text. Your glossary is good and well set out and the information displayed is quite easy to understand, however I would consider adding to this section as there were some other words throughout the page which were in need of a slight description. You have an excellent use of references which is great, but I would have another look at reference 11 as there is no text, only an arrow.

'''Abnormal vision'''

Your introduction is rather succinct which I like but I would encourage you to put references in this section. I would also suggest that you split it into 2 paragraphs to make it easier to read. Perhaps maybe you could put a photo of a normal eye in this section to show what it should look like, and then throughout the paper as you discuss the abnormal developments, you it could give the reader a better understanding as to how exactly this has altered the eye using the comparison.

The Normal eye development section is good as it provides a way for the reader to compare the differences in progression when referring to the different abnormalities listed below. However I would possibly suggest this to be put in a table, with perhaps a sentence at the top saying something along the lines of in order to fully comprehend abnormal development, an understanding of normal eye development is important - that way the reader can understand why you put this section in. I would also suggest a picture here.

The abnormal lens development section is clearly very well researched with a wide range of references. I like how you have separated the development in to the different sections of the eye as this can give a more thorough insight into these abnormalities. I think this section has been well written, and the only suggestion I would have would be in regards to the photo presented. Perhaps include some arrows to point at the sections you’re talking about and discuss what the nuclear area of the lens is?

The anormal corneal development and the abnormal retinal development are very descriptive and well referenced. I would perhaps look at moving the photo in the corneal development up a bit more and again I would provide more of a description of what is shown. If possible, I would try and make the abnormal retinal photo bigger.

Ocular manifestations is a bit confusing as im not sure if it’s a new heaing all together of if it is supposed to be part of the broad category of abnormalities. Your genetic section is well researched, I would just be careful in referencing the same paper too many times (25 is listed 5 times in this section) and perhaps try and find some other papers which compliment this research? I would probably put your reseach timeline at the bottome and include all of the treatment and clinical manifestation flowing on from each other. Note that in the research timeline, this is purely from one source, reference 26, and I would advise that you find alternative sources as well – im sure there would be individual research papers for each new date??

The anophthalmia section im assuming is still part of genetic abnormalities and I would recommend starting with the genes which are affected – to create a flow on effect. Other than that it is well references and easy to read. In regards to your photo I would have a description of what the photo is about in the enlarged view to assist with the readers comprehension. Also, at what point can these abnormalities be detected in the womb – either from an ultrasound or from sampling of the genes or something - and does this have an affect on whether the mother keeps the child or not? I think the environmental causes of abnormalities are good and I would suggest that you add photos here to break up the text and also to give us an understanding of what happens.

Finally, your glossary needs a fair few more words in there as to help with our understanding. You have many references which is great, however take a loot at 46 – 49 – they all seem to be the same? It would be appropriate to merge them into one reference.

===Lab 9 ===

'''1. 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.'''

<pubmed>21490060</pubmed>

This research paper wanted to determine if Cdk4 has a role in embryonic pancreas development. The study required embryos being harvested from mice (Cdk4+/+, Cdk4–/– and Cdk4R24C) 1 hour after the discovery of the vaginal plug. The results indicated that Cdk4 is needed for growth and morphogenesis of the developing pancreas. Cdk4 deficiency decreases the size of the pancreas due to diminished mesenchyme development and less Pdx1+ cells. The results allude to the fact that Cdk4 promotes the Beta cell growth from the signalling transcription factor E2f1 to assist in the proliferation of Ngn3+endocrine precursors. Cdk4 thus is seen as an imperative regulator of the early developmental stages of the pancreas which regulates the growth of the endocrine precursors and pancreatic progenitors.

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

The teeth development necessitates the epithelial/ mesenchymal interaction between the ectoderm of the first pharyngeal arch along with ectomesenchymal cells of the neural crest . The tooth bud is the name given to the collection of cells which will later form a tooth <ref><pubmed>12615136</pubmed></ref>. There are 3 sections which contribute to the [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00019-9&isbn=978-1-4377-2002-0&uniqId=369704599-2#4-u1.0-B978-1-4377-2002-0..00019-9--s0055| developing teeth]:
# The enamel organ: The cells of the inner enamel epithelium of the enamel organ form the ameloblasts which differentiates and produces the enamel.
# The dental papilla: This is formed by the neural crest and cells from an unknown origin <ref><pubmed>21425080</pubmed></ref>. These cells develop into odontoblasts (or dentin forming cells). The mesenchymal cells contribute to the formation of the tooth pulp.
# The dental follicle: This produces 3 different cells. Cementoblasts create the cementum of the tooth. The osteoblasts create the alveolar bone around the tooth roots. Finally, the fibroblasts form the periodontal ligaments which attach the teeth to the alveolar bone.

Therefore, the ectoderm, neural crest and mesoderm all contribute to the development of the tooth.

===References===
<references/>

User:Z3292017

2012-10-03T02:06:52Z

Z3292017: /* Lab Attendance */

=='''Lab Attendance'''==

Lab 1 - [[User:Z3292017|Z3292017]] 10:15, 25 July 2012 (EST)

Lab 2 - [[User:Z3292017|Z3292017]] 10:17, 1 July 2012 (EST)

Lab 3 - [[User:Z3292017|Z3292017]] 10:13, 8 August 2012 (EST)

Lab 4 - [[User:Z3292017|Z3292017]] 11:23, 15 August 2012 (EST)

Lab 5 - [[User:Z3292017|Z3292017]] 10:34, 22 August 2012 (EST)

Lab 6 - [[User:Z3292017|Z3292017]] 11:31, 29 August 2012 (EST)

Lab 7 - [[User:Z3292017|Z3292017]] 10:14, 12 September 2012 (EST)

Lab 8 - [[User:Z3292017|Z3292017]] 10:13, 19 September 2012 (EST)

Lab 9 - [[User:Z3292017|Z3292017]] 11:11, 26 September 2012 (EST)

Lab 10 - [[User:Z3292017|Z3292017]] 12:06, 3 October 2012 (EST)

==Lab 1 - [[User:Z3292017|Z3292017]]==

'''Lab 1 Online Assessment'''

''Question 1: Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique:''

The origin of IVF can be dated from the late 19th Century where embryo transplantation in rabbits was discovered by Walter Heape. The development of IVF was due to a cascade of events during the 20th century. Pincus and Enzmann from Harvard University suggested the possibility that mammalian eggs are able to develop normally in vitro in 1934. In 1948 Menken and Rock exposed 138 oocytes to spermatozoa in vitro. In 1959, Change was able to provide evidence for IVF by fertilising rabbit eggs with capicated sperm and thus achieve birth. From 1965 Robert Edwards attempted to fertilise human oocytes in vitro. In 1968 Edwards successfully fertilised a human egg using a human culture media he developed. Finally after years of research and failed attempts, the first test tube baby was born in 1978.
Robert Edwards was awarded the Nobel Prize in Physiology and Medicine in 2010 due to his immense development and contribution of IVF.

'''References'''
<references/>
#http://www.ivf-worldwide.com/ivf-history.html
#http://en.wikipedia.org/wiki/In_vitro_fertilisation
#http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/

''Question 2: Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings:''

Cleavage speed and implantation potential of early cleavage embryos in IVF or ICSI cycles by Lee, Lin and Hwu (July, 2012) attempted to determine the correlation of early embryo cleavage, its speed and the potential implantation rates for IVF. Their definition of early cleavage was embryonic mitosis occurring 25-27 hours after insemination. The embryos’ (day 3) cleavage speed was assessed and rated into 3 groups: rapid (more than 9 cells), normal (7-8 cells) and slow (less than 7 cells) along with their morphological quality being either good or poor. Normal fertilisation was determined by the presence of 2 nuclei and 2 polar bodies. 25-27 hours after IVF an early cleavage examination took place to determine which embryos had already cleaved. They embryos were then examined for their quality from 66-68 hours after IVF.

Early cleavage emrbyos developed normally in comparison to non early cleavage embryos. Notably, the early cleavage embryos produced a greater amount of “good quality” embryos and subsequently the implantation rate was sufficiently greater with early cleavage embryos. This finding is of great importance as embryo morphology is the most important tool to select the best embryo to transfer andthus increase the rates of implantation, pregnancy and live birth.

'''References'''

Lee MJ, Lee RK, Lin MH, Hwu YM '''Cleavage speed and implantation potential of early-cleavage embryos in IVF or ICSI cycles.''' J Assist Reprod Genet. 2012 Jul 25 PMID: 22825967

==Lab 2 - [[User:Z3292017|Z3292017]]==

'''Lab 2 Online Assessment'''

''Question 1: Image from journal source''

[[File:zygote.jpg]]

Zygotes showing different distribution of NPB in the 2PN and different PB alignment <ref>Alessia Nicoli, Francesco Capodanno, Lucia Moscato, Ilaria Rondini, Maria T Villani, Antonella Tuzio, and Giovanni B La Sala (2010) '''Analysis of pronuclear zygote configurations in 459 clinical pregnancies obtained with assisted reproductive technique procedures''' Department of Obstetrics and Gynecology, Arcispedale Santa Maria Nuova, Reprod Biol Endocrinol. 2010; 8: 77. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902489/?tool=pubmed NCBI]</ref>

===Reference===

<references/>

''Question 2: Identify a protein associated with the implantation process, including a brief description of the protein's role''

Proprotein convertase 6 (PC6) is a necessary regulatory molecule for embryo implantation which generates bioactive proteins such as growth factors, peptide hormones and adhesion molecules. It is produced in the uterine stromal cells in particular at the embryo attachment site throughout early pregnancy in mice. In order for implantation to occur, the uterus ungergoes morphological and physiological changes, one being differentiation of endometrial stromal cells.

Studies have shown that PC6 mRNA is upregulated in particularly at the site of embryo attachment in the mouse uterus, being predominantly at the antimesometrial pole undergoing decidualisation. These results imply that PC6 is associated with decidualisation. From this study, the researchers were able to determine that endometrial PC6 is imperative for maternal stromal decidual response for an implanting embryo during the time of implantation. They discovered that endometrial PC6 is produced explicitly in decidual cells (the vascular and cellular changes in a uterus in preparation for pregnancy) and is not found in other cells as well as the embryo. Similarly, they noted that inhibition of the production of PC6 early on (around day 3.5) using anti-PC6 MO blocked the decidualisation and thus impeded implantation. Notably, PC6 is produced in the late secretory phase of the menstrual cycle in preparation for implantation.

===Reference===

Guiying Nie, Ying Li, Min Wang, Yi Xun Liu, Jock K. Findlay and Lois A. Salamonsen '''Inhibiting Uterine PC6 Blocks Embryo Implantation: An Obligatory Role for a Proprotein Convertase in Fertility''' Biology of Reproduction April 1, 2005 vol. 72 no. 4 1029-1036. [http://www.biolreprod.org/content/72/4/1029.long Biology of Reproduction]

==Lab 3 - [[User:Z3292017|Z3292017]]==

'''Lab 3 Online Assessment'''

''Question 1: Difference between post fertilisation age and gestational age''

Post fertilisation age (embryonic age) is dated at fertilisation of the egg which is approximately 2 weeks after the gestational age. This however is far less easy to determine than the gestational age as they calculate the time of ovulation as the oocyte is normally fertilised within the 12 hour period after ovulation.

Gestational age is the date of the beginning of the last normal menstrual period and is clinically more commonly used as it is a much easier method to calculate. Notably, the crown-rump length of the fetus along with the head and femur length are later used to confirm the estimated age of the fetus.

[http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00005-9--s0050&isbn=978-1-4377-2002-0&uniqId=351438666-2#4-u1.0-B978-1-4377-2002-0..00005-9--s0075| Estimation of gestational and embryonic age]

''Question 2: 3 different types of tissues formed from somites''

Ventromedially, the somite differentiates into the sclerotome which forms the vertebrae and the ribs. Studies have shown that Pax-1 is essential for the ventral sclerotome differentiation. The sclerotome differentiates into the vertebrae and ribs through bone formation. [http://www.ncbi.nlm.nih.gov/pubmed/8026324 Role of Pax-1 in skeleton development]. This is primarily initiated with mesenchymal cells which assists the formation of the pre-cartilage mass via chrondrocytes and subsequently cartilage formation. Bone then develops through the replacement of cartilaginous tissue with bone tissue. [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00014-X&isbn=978-1-4377-2002-0&uniqId=351438666-4 Development of bone and cartilage]

Dorsolaterally, the somite first differentiates into the dermomyotome which then creates 2 regions. The myotome region forms primordial muscle cells (myoblasts) and the dermatome region forms the fibroblasts (dermis). [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00015-1&isbn=978-1-4377-2002-0&uniqId=351438666-4#4-u1.0-B978-1-4377-2002-0..00015-1 Development of Muscle]

Dermatome along with Neurotrophin-3 assists with the early formation of the dermis. [http://www.ncbi.nlm.nih.gov/pubmed/7671821 Role of Neurotrophin-3] The dermal papillae consist mainly of fibroblasts and is located close to the epidermis. It contains both elastin and collagen fibres (produced by fibroblasts) with the elastin fibres perpendicular to the surface of the skin. The reticular dermis accounts for the majority of the dermis with multidirectional elastin and collagen fibres. Notably, in the dermal papillae, a plexus consisting of numerous blood vessels are found but do not penetrate into the epidermis. Some nerves within this region do penetrate through to the epidermis via free nerve endings which are linked to nerve corpuscles, such as Meissner's plexus. [http://www.skin-science.com/_int/_en/topic/topic_sousrub.aspx?tc=SKIN_SCIENCE_ROOT%5EAN_ORGAN_REVEALED%5ETHE_DERMIS&cur=THE_DERMIS Dermis formation]

Myotomes are separated into [http://embryology.med.unsw.edu.au/embryology/index.php?title=Musculoskeletal_System_-_Muscle_Development#Myotome epaxial muscles and hypaxial muscles] via primordial muscle cells . The epaxial muscles form the skeletal muscles dorsal to the vertebral column known as the erector spinae muscles. The hypaxial muscles form the ventral skeletal muscles which contribute to the lung and limb formation. The skeletal muscle fiber is long, cylindrical and multinucleated, with peripherally located nuclei.

==Lab 4 - [[User:Z3292017|Z3292017]]==

'''Lab 4 Online Assessment'''

''Question 1: 2 invasive prenatal diagnostic techniques related to the placenta:''

1. Amniocentesis:

A relatively common yet invasive procedure normally conducted between weeks 15-18 of gestation. A 22 gauge needle is inserted through the anterior abdominal and uterine walls (around the region of the umbilicus) of the mother into the amniotic cavity. Of the approximate 200mL volume that the mother is carrying at this early stage of pregnancy, only 15-20mL can be withdrawn safely. There is usually little risk when performing this procedure as an ultrasonography can be used concurrently to outline the fetal and placental position.

Amniocentesis is a procedure used to determine many genetic disorders such as Down Syndrome and also neural tube defects such as spina bifida cystica. [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00006-0--s0100&isbn=978-1-4377-2002-0&uniqId=352651422-2#4-u1.0-B978-1-4377-2002-0..00006-0--s0110| Amniocentesis - The Developing Human]

2. Chorionic Villus Sampling:

Trophoblastic tissue biopsies between 5-20 mg can be obtained through inserting a needle through the abdominal and uterine walls of the mother into the uterine cavity. This can also be completed transcervically using a polyethylene catheter through the cervix to obtain a chorionic villus sample. There is a slightly greater risk of miscarriage after this procedure has been performed when compared to amniocentesis (of around 1%).

Chorionic villus sampling is a procedure used to detect chromosomal abnormalities and also X linked disorders. The benefit of CVS over amniocentesis is that it can be performed between the 10th-12th week of gestation and thus giving an earlier diagnosis. [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00006-0--s0100&isbn=978-1-4377-2002-0&uniqId=352651422-2#4-u1.0-B978-1-4377-2002-0..00006-0--s0125| Chorionic Villus Sampling - The Developing Human]

''Question 2: Paper using cord stem cell therapeutically discussion of findings:''

Lim JY, Jeong CH, Jun JA, Kim SM, Ryu CH, Hou Y, Oh W, Chang JW, Jeun SS '''Therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of cerebral ischemia''' Stem Cell Res Ther. 2011; 2(5): 38 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3308035/?tool=pubmed| PMID: 21939558]

In this paper, the researchers investigated the effects of therapeutic potential of mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of stroke. Following this, the researchers then investigated whether the mesenchymal stem cells could enter and survive in the brain, and their potential to improve post stroke functional recovery. Mesenchymal stem cells (MSC) are a promising therapeutic strategy for the treatment of stroke due to their high proliferative capacity and also that they can be easily obtained.

The mesenchymal stem cells were injected intrathecally in some rats and intravenously in the others three days after Middle Coronary Artery Occlusion (MCAO) using isoflurane anesthesia. A 1cm incision was made over L3-L5 spinous processes and a neonatal lumbar puncture needed (25 gauge) was inserted into the spinal canal. MSCs (1 × 10^6) was diluted with 20 μl PBS being injected into the CSF over 30 seconds. Intravenously, MSCs (1 × 10^6) was diluted with 700 μl PBS were injected slowly for five minutes via an intravenous cannula situated in the tail vein. The presence and survival of the MSCs in the brain tissue was examined by immunohistochemistry. The rats were examined by their recovery of coordination of movement using both the Rotarod test and the adhesive removal test after the 1st, 2nd, 3rd and 4th week of stroke.

The results indicated that the MSC intrathecally receiving rats had an increased level of migrated cells to the ischemic area compared to the intravenous administration of MSCs. Additionally, many of the cells were expressing the mature neural lineage markers. Overall, the intrathecal administration of MSCs were more effective in reducing ischemic damage, yet proved to be similar to intravenous administration in promoting neurological recovery.

This study thus indicated a potential treatment for cerebral ischemia or neurodengerative disorders due to its ability to recover ischemic damaged tissue.

== Lab 7 ==

'''Lab 7 Online Assessment'''

''Question 1''

''(a) Definition of muscle satellite cell''

A muscle satellite cell is a quiescent mononucleated cell, which respond to injury by proliferating to form regenerated muscle and additional satellite cells, found between the basement membrane of specialised muscle fibres. [http://www.ncbi.nlm.nih.gov/pubmed/12757751| Muscle Satellite Cell PMID: 12757751]

''(b) Two examples of when satellite cells are activated''

Satellite cells are employed for skeletal muscle trauma and also disease.

* Muscle injury: When muscle injury occurs, the satellite cells are activated and will either form multinucleated myotubes to assist with muscle regeneration, or will form additional quiescent satellite cells in order to assist with more [http://www.ncbi.nlm.nih.gov/pubmed?term=The%20muscle%20satellite%20cell%20at%2050%3A%20the%20formative%20years| muscle regeneration]. Sambasivan et al. indicated in their 1993 study that other cells with regenerative potential depend on the satellite cell presence especially the Pax7 expressing satellite cells. [http://dev.biologists.org.wwwproxy0.library.unsw.edu.au/content/138/17/3647| Pax7-expressing satellite cells]

* Muscle disease: Research has shown that congenital myopathies such as Duchenne Muscular Dystrophy lead to a greater number of satellite cells than in normal muscle cells. Notably, the regenerative capacity of, for example Duchenne Muscular Dystrophy, is limited due to the severity and continuation of the disease. [http://genesdev.cshlp.org.wwwproxy0.library.unsw.edu.au/content/20/13/1692| Muscle stem cells in development, regeneration, and disease]

''Question 2: 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''

Spinal cord injury will result in partial or complete paralysis of the muscle innervation at or below the trauma level of the spinal cord resulting in atrophy. Some studies have noted that a some paralysed muscles due to spinal cord injury have an increase in force per cross sectional area of the muscle compared to normal in an attempt to maintains the muscle's normal strength. However, it is also important to note, the muscle cross sectional area significantly decreased. Due to the decrease in muscle, the study also indicated that there were increased levels of connective tissues and fat - thought to transfer more of the force to the tendon. Importantly, in chronic muscle denervation (greater than 50% of muscle size loss), the strength of the muscle (if there was any at all) has seriously deteriorated. [http://www.ibib.waw.pl/bbe/bbefulltext/bbe_25_3_039_ft.pdf| Muscle Atrophy after Human Spinal Cord Injury]

After a spinal cord injury the muscle fibre type pattern changes from a mix of type I and type II to predominantly type II fast glycolytic fibres. This is thought be an explanation of the quick muscle fatigue noted in rehabilitation. Notably, Burnham et al. discovered that the muscle fibre type change occurs in stages rather than an immediate effect and thus opens the door to more research to prevent the transformation of the muscle types from occurring, which is inidcated to be done within the first week or two following spinal cord injury. [http://www.ncbi.nlm.nih.gov/pubmed/9044514| Skeletal muscle fibre type transformation following spinal cord injury]

==Lab 8==

'''Lab 8 Online Assessment'''

'''Vision'''

The photo at the top of your page is a great choice and makes the site that much more appealing. The only suggestion I would have here is to potentially minimise the photo as it makes the contents section to the left of it hard to read. Your introduction is clear and concise and gives a good description of the eye. A slight adjustment I would make is perhaps to make it slightly longer giving a brief discussion about what is to be discussed on this page. Included in your introduction you have the anatomy of the eye. Firstly, would it be appropriate to include the histology as well, as it appears further down the page you discuss the cells, so perhaps if you gave a brief histological overview that could make the sections below easier for the reader to comprehend. I would probably add to that that if you were to include histology, to put the anatomy and histology into a new section just so it doesn’t clutter the introduction.

Your history, although I’m aware it ins’t finished, would read better if it were in a table and would also bring some more colour to the page. I’m assuming this will come when you finish this section, but it would be wise to include updated examples as well in order to show an adequate progression of the history.

The development section appears to be very thorough which is fantastic. It is rather clear that you have put a lot of research and time into this section. The introduction you have there is well written and again concise which is great. Additionally I like your use of photos just below it to further your explanation and also to break up the text. In regards to your photos, I would suggest perhaps a better description of them and to make sure you include where you got the photo from. If there were an explanation of the photo in simplistic terms, then I think the photos would be really beneficial.

The optic nerve section is well written but it appears to lack references?? In the first 3 paragraphs there are only 2 references. I would probably suggest that this information is backed up by additional sources as well. Also, with your hand drawn pictures (which are good), I would suggest an explanation on them when you open the picture up in another window. Your paragraph describing the 2 pictures, I would probably recommend that it become sintegrated within the text i.e. when you are talking about that part of it then include it there. I just think it would make it flow better that way – like you have done with figure 3.

The retina is good and well set out with pictures. However I noticed that you have used the exact references as before (3, 4)?? It would be really advisable to include many more references than what is listed. The same applies to the images as I said above, but good integration!

The ciliary body appears to be well researched and referenced. From the iris down there appears to be a lack of new references and also looks rather bland - so here I would suggest including additional photos from journal articles you have used. Also, it seems rather brief, I’m wondering whether there is more information about the embryological processes that could be included?

The current research is a good start, but there isn’t much of an explanation of the photo that is included and brief discussion of the research should probably be included. Are there additional research projects to include as well?

Finally, your references ar good but short. The fisrt 2 need to be put in the appropriate format. I would definitely suggest including many more references in order to make your information listed more valid.

'''Somatosensory development'''

I really like your introduction, I think that is is really informative and gives the reader a much clearer understanding of what this topic is about. Your references here need to be included in the reference section below but it appears that you have a good amount of references for the points depicted. At the end of the first paragraph it discusses a picture of the general organisation however there is not one there?? Also the inclusion of a picture would be agreat idea not only to further our understanding but also to break up the text and make it more appealing.

In your history of discoveries section I would probably recommend putting this in a colourful table, again to rbeak up the text, and also to make it easier to read. I would probably suggest here that you include a greater progression of discoveries to show the change of thinking over time. Note to also inlduce the appropriate referencing as shown in previous lab classes.

The central somatosensory differentiation is very expansive and informative. I would assume that you have put a lot of research into this section. Note that you have used pretty well the same references over and over. I would suggest that you include additional references to back up those statements as well. If those couple of references were the only ones saying that information, then I would suggest further researching to ensure that other journal articles don’t contradict this. The image is good and appears to show a good somatosensory pathway, however I would make the font bigger, so that it would not be imperative to enlarge the photo to read what is there. The picture has a discription when it is enlarged which is good, but I think it would also be appropriate to put the correct student information for the referencing.

In the Touch part, I noted that almost none of the text is refenced, which essentially makes the information listen invalid, so I would look into finding appropriate references here. Also, this section seems a bit dull with no pictures. Perhaps histological photos could be included here? I know we studied them in histology and this would make the section more interesting and also compliment the information stated. I would also suggest that those subheadings you don’t want in bold, you list in italic with two ‘ ‘ in order to separate it from the text below..

The Pain section probably needs to be set out better by using dot points? It appears that you have provided some excellent information but it is also important to put the references included with the reference section below. A photo here might be nice, perhaps of the different fibres if this can be found?

The Hot/Cold section is better set out and I like the appropriate referencing here. However, it appears that you are re-using the same references, so I would suggest some more research be done here to compliment your other references. It is better set out, however I would suggest some photos to be included if at all appropriate and can be found.

Pressure is similar to the pain section in the sense that the references really need to be put in the referencing section. It would also be advisable that you split the first paragraph up as it is rather long and not very appealing for one to read.

Current research section is good and concise. I like the use of the picture there, and I like the description that you have when you enlarge the picture. Is there any other current research happening now?

Finally, I would suggest adding more information outlining the development of these areas as I believe this to have been limited across the majority of sections. Although you are providing good reaseach and information describing these sections, as this is am embryology course, I would see it as appropriate that some sort of developmental progression is included – or if this is not known as of yet, for that to be stated. I would also highly recommend that you include a detailed glossary of words, as this is rather incomplete.

'''Taste development'''

The introduction section is very informative and I like the picture included discussing the 5 basic tastes which is interesting to read. I really enjoy your descriptions of bitter and sweet and find it interesting to read. I like the research you included in this section but I believe this needs to be referenced. Currently in the introduction you have only 1 references, so I would suggest that you find more to further validate your information (note that there are no references in the first paragraph). I like in your picture that you included a description. The cell biology section I would probably put in its own section with = = to break up the contend displayed. In this section it is clear that this has been researched however there have been no references listed at all here.

The taste map section has clearly been well researched yet poorly referenced. It would be interesting to look at if possible a progression of the understanding of the taste map. In the picture of the tongue, I would suggest that it has a better description on the enlarged image. However, some of this text is rather hard to read, such as the descriptions of the first and second order neurons. As you have included terms in there which would be foreign to most people, I would try to include either a picture to show exactly where these parts are such as the NTS which can give the reader a better understanding of what you’re saying. Note that you say things like “copious scientific conjecture surrounds…” however there is no references here! This section is well researched which is great, but I would really consider putting it into slightly easier terms to better comprehension.

In the cortical areas section, a similar approach applies: when describing locations of things such as the I/fO, you should really include a clear diagram as to where all of these are. I can see you included the section of the brain however don’t see it as too informative so a better description there would be appropriate. I would also note that you are repeating your references again, and it would be advisable that you find alternative information to include as well.

The timeline section is very informative and really stands out. I’m assuming you will be including the photos later this week. This is well written and gives a truly informative description of the embryological changes that occur. It will look much better and be better to understand once the photos have been included. Note that you have used the same references pretty well the whole time in this section. Although that paper may have a lot of information about what you are needing to talk about, I would also encourage you to research more papers in order to compliment the information you have listed.

The history of discoveries section is well set out and clear and concise. In some areas I would suggest a brief descripton of what you have written such as “PKD2L”, and also make sure you include the appropriate references as all I can see currently it numbers.

In the adult tongue and taste bud section, is this also what the tongue looks like from week 15? If not what changes occurs for it to form into what you have described as the adult tongue and what enhances these changes? This section is informative however it is really lacking references. The taste bud picture you have is quite good, but is that also what the taste bud looks like at 15 weeks?

The abnormalities section is really interesting and is rather enjoyable to read. Are they the only abnormalities that can happen to the tongue? How about environmental? Does alcohol, smoking or drugs affects its development of either the tongue or the taste buds? Additonally, your current research is very thorough and interesting. In regards to the photos you have there, I would make sure that they are set out appropriately, with the information that this is a student project.

Finally, the glossary needs to be highlighted to make it stand out and more words need to be included. Note that in your references, reference 5 can not be accessible, so make sure you fix that up. Overall, it was interesting to read and I enjoyed the display of photos that were also included!

'''Olfaction'''

Your introduction is good and concise giving a simple understanding of the olfactory system. Here I would suggest that you include what you’re about to discuss on the page. I also think you should include some references and maybe a photo in this section. The references to show that this information has been researched and the photo to break up the text and give the reader a simple understanding of the olfactory system.

The history of discovery section is clearly well researched and is well set out. However, I would suggest that you include brief descriptions of what has been described such as the Vomeronasal organ or the Nobel Prize which will further enhance the readers understanding. You have a good use of references there as well. In the picture that was included in this section, I would provide a more indepth description of what is drawn i.e. what the ectoderm is etc.

The timeline of developmental process is really well set out and easy to read. I would just make sure that every new point you include, you put it with a references as some of your points are not referenced at all and you need to be careful of that! I would also suggest that you put it in appropriate bullet points using the star key on your keyboard, that way it can be set out a bit better. Also, at the end of week 8, does this mean the olfactory system is complete by then? If so, then I would suggest you state that in that final week, if not, then what other small changes occur throughout the duration of the pregnancy? Also note that week 6 – 8 the references are either limited or not there, so I would recommend putting them in.

The anatomy of the olfactory system and the normal function are limited in information but also have only one reference between them. The images attached should really have more of a description when the picture is enlarged to give the reader a better understanding of what you’re talking about. Such as: diagram of olfactory bulb- what does it do and where is it located?

The abnormality section is rather indepth for 2 conditions, are there any other factors that come into play in regards to olfactory defects? Such as environmental? The Kallmann’s syndrome is really indepth and describes the clinical features, diagnosis and treatment, could this also be implementd with the Choanal atresia? Or are the same techniques used there? Also, be careful when you use shortening of words such as OB, you provided the HH in brackets first, so I would suggest the same is done with the olfactory bulb just to prevent confusion. I like your use of both images and give s a simple but good explanation of what you have been discussing (and also breaks up the text!). I like how you have provided a good description in the enlarged picture and it makes it easier for the reader to understand.

The current research section really shows that you have put a lot of effort in for this section. However, at the beginning of each new research you state either a study or a paper with a link, perhaps use the name of the paper and who wrote it and use that as the link instead. It is really interesting and I rather enjoyed reading it, however, if possible I would add some more photos just to break up the text. Your glossary is good and well set out and the information displayed is quite easy to understand, however I would consider adding to this section as there were some other words throughout the page which were in need of a slight description. You have an excellent use of references which is great, but I would have another look at reference 11 as there is no text, only an arrow.

'''Abnormal vision'''

Your introduction is rather succinct which I like but I would encourage you to put references in this section. I would also suggest that you split it into 2 paragraphs to make it easier to read. Perhaps maybe you could put a photo of a normal eye in this section to show what it should look like, and then throughout the paper as you discuss the abnormal developments, you it could give the reader a better understanding as to how exactly this has altered the eye using the comparison.

The Normal eye development section is good as it provides a way for the reader to compare the differences in progression when referring to the different abnormalities listed below. However I would possibly suggest this to be put in a table, with perhaps a sentence at the top saying something along the lines of in order to fully comprehend abnormal development, an understanding of normal eye development is important - that way the reader can understand why you put this section in. I would also suggest a picture here.

The abnormal lens development section is clearly very well researched with a wide range of references. I like how you have separated the development in to the different sections of the eye as this can give a more thorough insight into these abnormalities. I think this section has been well written, and the only suggestion I would have would be in regards to the photo presented. Perhaps include some arrows to point at the sections you’re talking about and discuss what the nuclear area of the lens is?

The anormal corneal development and the abnormal retinal development are very descriptive and well referenced. I would perhaps look at moving the photo in the corneal development up a bit more and again I would provide more of a description of what is shown. If possible, I would try and make the abnormal retinal photo bigger.

Ocular manifestations is a bit confusing as im not sure if it’s a new heaing all together of if it is supposed to be part of the broad category of abnormalities. Your genetic section is well researched, I would just be careful in referencing the same paper too many times (25 is listed 5 times in this section) and perhaps try and find some other papers which compliment this research? I would probably put your reseach timeline at the bottome and include all of the treatment and clinical manifestation flowing on from each other. Note that in the research timeline, this is purely from one source, reference 26, and I would advise that you find alternative sources as well – im sure there would be individual research papers for each new date??

The anophthalmia section im assuming is still part of genetic abnormalities and I would recommend starting with the genes which are affected – to create a flow on effect. Other than that it is well references and easy to read. In regards to your photo I would have a description of what the photo is about in the enlarged view to assist with the readers comprehension. Also, at what point can these abnormalities be detected in the womb – either from an ultrasound or from sampling of the genes or something - and does this have an affect on whether the mother keeps the child or not? I think the environmental causes of abnormalities are good and I would suggest that you add photos here to break up the text and also to give us an understanding of what happens.

Finally, your glossary needs a fair few more words in there as to help with our understanding. You have many references which is great, however take a loot at 46 – 49 – they all seem to be the same? It would be appropriate to merge them into one reference.

===Lab 9 ===

'''1. 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.'''

<pubmed>21490060</pubmed>

This research paper wanted to determine if Cdk4 has a role in embryonic pancreas development. The study required embryos being harvested from mice (Cdk4+/+, Cdk4–/– and Cdk4R24C) 1 hour after the discovery of the vaginal plug. The results indicated that Cdk4 is needed for growth and morphogenesis of the developing pancreas. Cdk4 deficiency decreases the size of the pancreas due to diminished mesenchyme development and less Pdx1+ cells. The results allude to the fact that Cdk4 promotes the Beta cell growth from the signalling transcription factor E2f1 to assist in the proliferation of Ngn3+endocrine precursors. Cdk4 thus is seen as an imperative regulator of the early developmental stages of the pancreas which regulates the growth of the endocrine precursors and pancreatic progenitors.

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

The teeth development necessitates the epithelial/ mesenchymal interaction between the ectoderm of the first pharyngeal arch along with ectomesenchymal cells of the neural crest . The tooth bud is the name given to the collection of cells which will later form a tooth <ref><pubmed>12615136</pubmed></ref>. There are 3 sections which contribute to the [http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00019-9&isbn=978-1-4377-2002-0&uniqId=369704599-2#4-u1.0-B978-1-4377-2002-0..00019-9--s0055| developing teeth]:
# The enamel organ: The cells of the inner enamel epithelium of the enamel organ form the ameloblasts which differentiates and produces the enamel.
# The dental papilla: This is formed by the neural crest and cells from an unknown origin <ref><pubmed>21425080</pubmed></ref>. These cells develop into odontoblasts (or dentin forming cells). The mesenchymal cells contribute to the formation of the tooth pulp.
# The dental follicle: This produces 3 different cells. Cementoblasts create the cementum of the tooth. The osteoblasts create the alveolar bone around the tooth roots. Finally, the fibroblasts form the periodontal ligaments which attach the teeth to the alveolar bone.

Therefore, the ectoderm, neural crest and mesoderm all contribute to the development of the tooth.

===References===
<references/>

File:Cochlear Implant.jpg

2012-10-03T01:57:51Z

Z3292017:

Description:

Reference: http://www.nidcd.nih.gov/health/hearing/pages/coch.aspx

Copyright: National Institute on Deafness and Other Communication Disorders at the National Institutes of Health. Unless otherwise stated, the information on this site is not copyrighted and is in the public domain. It is free for the public to use, copy, and distribute. You may encounter documents that were sponsored along with private companies or other organizations. Those documents will have statements that protect them under U.S. and foreign copyright laws.

File:Cochlear Implant.jpg

2012-10-03T01:57:28Z

Z3292017: Description: Copyright: National Institute on Deafness and Other Communication Disorders at the National Institutes of Health. Unless otherwise stated, the information on this site is not copyrighted and is in the public domain. It is free for the public

Description:

Copyright: National Institute on Deafness and Other Communication Disorders at the National Institutes of Health. Unless otherwise stated, the information on this site is not copyrighted and is in the public domain. It is free for the public to use, copy, and distribute. You may encounter documents that were sponsored along with private companies or other organizations. Those documents will have statements that protect them under U.S. and foreign copyright laws.

2012 Group Project 6

2012-10-03T01:56:03Z

Z3292017: /* Technologies to overcome the problems */

[[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 name="PMID11314703"><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 name="PMID11314703><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. <ref name="PMID16269359"><pubmed>16269359</pubmed></ref> <ref><pubmed>11237469</pubmed></ref>

[[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. <ref name="PMID16269359"/>

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. <ref name="PMID16269359"/> <ref><pubmed>21774850</pubmed></ref>

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==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|400px]]

The development of ear is attributed to the pharyngeal arches one and two. 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. <ref><pubmed>11698185</pubmed></ref>

===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 name="PMID10976045"><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 name="PMID10976045"/> <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"/>

'''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.

[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]
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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle]]

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'''
[[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>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them.

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.

====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>PMC3335728</pubmed></ref>.

|}

'''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 <ref><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* 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 <ref><pubmed>84910</pubmed></ref>.
* 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 <ref><pubmed>5949097</pubmed></ref>. 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 <ref>pubmed>PMC1792732</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* 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.

|- 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 <ref><pubmed>3067168</pubmed></ref>
* 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''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 <ref><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 <ref><pubmed>12795509</pubmed></ref>.
* Finally, the central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing<ref><pubmed>9161611</pubmed></ref>.

|- 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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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:Newborn_hearing_test.jpg|thumb |automated auditory response technology (AABR)]]

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>

[[Image:Cochlea.jpg]]

[[File:Cochlear_Implant.jpg|x250px]]

<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

*'''Nonsyndromic deafness''': Hearing impairment not affiliated with other signs or symptoms

*'''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

*'''Syndromic deafness''': Hearing impairment occurring with additional abnormalities in the body

*'''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

2012-10-03T01:33:40Z

Z3292017: /* Genetic */

[[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 name="PMID11314703"><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 name="PMID11314703><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. <ref name="PMID16269359"> <pubmed>16269359</pubmed></ref> <ref><pubmed>11237469<pubmed></ref>

[[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. <ref name="PMID16269359"/>

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. <ref name="PMID16269359"/> <ref><pubmed>1315292</pubmed></ref>

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==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|400px]]

The development of ear is attributed to the pharyngeal arches one and two. 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. <ref><pubmed>11698185</pubmed></ref>

===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 name="PMID10976045"><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 name="PMID10976045"/> <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"/>

'''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.

[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]
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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle]]

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'''
[[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>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them.

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.

====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>PMC3335728</pubmed></ref>.

|}

'''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 <ref><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* 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 <ref><pubmed>84910</pubmed></ref>.
* 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 <ref><pubmed>5949097</pubmed></ref>. 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 <ref>pubmed>PMC1792732</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* 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.

|- 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 <ref><pubmed>3067168</pubmed></ref>
* 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''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 <ref><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 <ref><pubmed>12795509</pubmed></ref>.
* Finally, the central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing<ref><pubmed>9161611</pubmed></ref>.

|- 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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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>

[[Image:Cochlea.jpg]]

<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

*'''Nonsyndromic deafness''': Hearing impairment not affiliated with other signs or symptoms

*'''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

*'''Syndromic deafness''': Hearing impairment occurring with additional abnormalities in the body

*'''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

2012-10-03T01:30:37Z

Z3292017: /* Glossary */

[[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 name="PMID11314703"><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 name="PMID11314703><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. <ref name="PMID16269359"> <pubmed>16269359</pubmed></ref> <ref><pubmed>11237469<pubmed></ref>

[[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. <ref name="PMID16269359"/>

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. <ref name="PMID16269359"/> <ref><pubmed>1315292</pubmed></ref>

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==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|400px]]

The development of ear is attributed to the pharyngeal arches one and two. 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. <ref><pubmed>11698185</pubmed></ref>

===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 name="PMID10976045"><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 name="PMID10976045"/> <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"/>

'''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.

[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]
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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle]]

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'''
[[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>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them.

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.

====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>PMC3335728</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 <ref><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* 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 <ref><pubmed>84910</pubmed></ref>.
* 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 <ref><pubmed>5949097</pubmed></ref>. 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 <ref>pubmed>PMC1792732</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* 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.

|- 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 <ref><pubmed>3067168</pubmed></ref>
* 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''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 <ref><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 <ref><pubmed>12795509</pubmed></ref>.
* Finally, the central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing<ref><pubmed>9161611</pubmed></ref>.

|- 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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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>

[[Image:Cochlea.jpg]]

<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

*'''Nonsyndromic deafness''': Hearing impairment not affiliated with other signs or symptoms

*'''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

*'''Syndromic deafness''': Hearing impairment occurring with additional abnormalities in the body

*'''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

2012-10-03T01:23:18Z

Z3292017: /* Genetic */

[[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 name="PMID11314703"><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 name="PMID11314703><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. <ref name="PMID16269359"> <pubmed>16269359</pubmed></ref> <ref><pubmed>11237469<pubmed></ref>

[[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. <ref name="PMID16269359"/>

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. <ref name="PMID16269359"/> <ref><pubmed>1315292</pubmed></ref>

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==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|400px]]

The development of ear is attributed to the pharyngeal arches one and two. 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. <ref><pubmed>11698185</pubmed></ref>

===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 name="PMID10976045"><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 name="PMID10976045"/> <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"/>

'''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.

[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]
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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle]]

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'''
[[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>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them.

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.

====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>PMC3335728</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 <ref><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* 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 <ref><pubmed>84910</pubmed></ref>.
* 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 <ref><pubmed>5949097</pubmed></ref>. 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 <ref>pubmed>PMC1792732</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* 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.

|- 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 <ref><pubmed>3067168</pubmed></ref>
* 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''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 <ref><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 <ref><pubmed>12795509</pubmed></ref>.
* Finally, the central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing<ref><pubmed>9161611</pubmed></ref>.

|- 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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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>

[[Image:Cochlea.jpg]]

<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

2012-10-03T01:21:13Z

Z3292017: /* Genetic */

[[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 name="PMID11314703"><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 name="PMID11314703><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. <ref name="PMID16269359"> <pubmed>16269359</pubmed></ref> <ref><pubmed>11237469<pubmed></ref>

[[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. <ref name="PMID16269359"/>

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. <ref name="PMID16269359"/> <ref><pubmed>1315292</pubmed></ref>

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==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|400px]]

The development of ear is attributed to the pharyngeal arches one and two. 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. <ref><pubmed>11698185</pubmed></ref>

===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 name="PMID10976045"><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 name="PMID10976045"/> <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"/>

'''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.

[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]
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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle]]

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'''
[[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>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them.

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.

====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>PMC20301595</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 <ref><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* 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 <ref><pubmed>84910</pubmed></ref>.
* 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 <ref><pubmed>5949097</pubmed></ref>. 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 <ref>pubmed>PMC1792732</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* 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.

|- 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 <ref><pubmed>3067168</pubmed></ref>
* 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''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 <ref><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 <ref><pubmed>12795509</pubmed></ref>.
* Finally, the central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing<ref><pubmed>9161611</pubmed></ref>.

|- 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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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>

[[Image:Cochlea.jpg]]

<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

2012-10-03T01:12:39Z

Z3292017: /* Genetic */

[[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 name="PMID11314703"><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 name="PMID11314703><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. <ref name="PMID16269359"><pubmed>16269359</pubmed></ref>

[[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. <ref name="PMID16269359"/>

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. <ref name="PMID16269359"/>

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==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|400px]]

The development of ear is attributed to the pharyngeal arches one and two. 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. <ref><pubmed>11698185</pubmed></ref>

===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 name="PMID10976045"><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 name="PMID10976045"/> <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"/>

'''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.

[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]
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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle]]

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'''
[[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>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them.

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.

====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>PMID20301595</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 <ref><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* 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 <ref><pubmed>84910</pubmed></ref>.
* 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 <ref><pubmed>5949097</pubmed></ref>. 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 <ref>pubmed>PMC1792732</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* 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.

|- 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 <ref><pubmed>3067168</pubmed></ref>
* 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''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 <ref><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 <ref><pubmed>12795509</pubmed></ref>.
* Finally, the central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing<ref><pubmed>9161611</pubmed></ref>.

|- 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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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>

[[Image:Cochlea.jpg]]

<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

2012-10-03T01:09:53Z

Z3292017: /* Genetic */

[[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 name="PMID11314703"><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 name="PMID11314703><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. <ref name="PMID16269359"><pubmed>16269359</pubmed></ref>

[[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. <ref name="PMID16269359"/>

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. <ref name="PMID16269359"/>

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==

[[File:Pharyngeal_arch_one_and_two_in_mice.png|thumb|400px]]

The development of ear is attributed to the pharyngeal arches one and two. 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. <ref><pubmed>11698185</pubmed></ref>

===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 name="PMID10976045"><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 name="PMID10976045"/> <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"/>

'''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.

[[File:otic placode embryo.jpg|left|thumb|250px|Otic placode of an embryo]]
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"/>

* ''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>
[[File: otic vesicle.jpg|left|thumb|200px| Zebrafish otic vesicle]]

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'''
[[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>

'''Formation of inner ear structures'''

Further development of the inner ear occurs as the otic vesicle differentiates into the membranous labyrinth. This is a continuous structure, surrounded by an otic capsule. The otic capsule is mesoderm derived from the base of the skull and will later chondrify, holding the organs of balance and hearing, as well as the cranial nerve associated with them.

'''1''' ''Semi-circular canals''

As reviewed by Carey and Amin (2006), the semi-circular canals - the organ of balance, also known as the vestibular apparatus - develops from the superior surface of the otocyst. This occurs as the cranial end elongates as 3 little expansions, with the remainder forming the utricle.<ref><pubmed>16552774</pubmed></ref>

[[File: cochlea stereocilia bundle.jpg|left|thumb|250px|Stereocilia bundles in the normal cochlea]]

'''2''' ''Cochlea''

The cochlea - the organ of hearing - develops from the inferior surface of the otocyst, as reviewed by Fritzsch ''et al''. (2011). <ref name="PMID21256948"><pubmed>21256948</pubmed></ref> This occurs as the caudal end elongates and curves 2.5 times (in humans), forming the cochlear duct; the remainder forms the saccule.<ref name="PMID21256948"/> Growth of the cochlear duct is controlled by the growth of the organ of Corti, which itself depends upon hair cell development <ref><pubmed>18579736</pubmed></ref>. At first, a simple epithelium is still present within the cochlear duct, however, at a later stage we will see the distinct differentiation of epithelium into stereocilia hair cells, the organ of Corti and the saccular macula.<ref name="PMID21256948"/> <ref><pubmed>16145671</pubmed></ref>

'''3''' ''Vestibulocochlear nerve (CN VIII)''

During its development, this cranial nerve receives contribution from the otocyst and cranial neural crest cells. It contains bipolar neurons, vestibular neurons and cochlear neurons.

====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 <ref><pubmed>3041362</pubmed></ref>.
* 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” <ref><pubmed>16311017</pubmed></ref> <ref><pubmed>12454967</pubmed></ref>
* 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 <ref><pubmed>84910</pubmed></ref>.
* 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 <ref><pubmed>5949097</pubmed></ref>. 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 <ref>pubmed>PMC1792732</pubmed></ref>.
* 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 <ref><pubmed>11017784</pubmed></ref>. 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 <ref><pubmed>9792846</pubmed></ref>.
* Hearing loss is considered the most frequent defect of congenital Rubella followed by mental retardation <ref><pubmed>19111256</pubmed></ref>.
* 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.

|- 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 <ref><pubmed>3067168</pubmed></ref>
* 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 <ref><pubmed>22519989</pubmed></ref>.
* 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 <ref><pubmed>16192480</pubmed></ref>.
* 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 <ref><pubmed>19766534</pubmed></ref>.

|}

'''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 <ref><pubmed>9161611</pubmed></ref>:
## Developmental delay in auditory maturation
## Sensorineural hearing loss
## Intermittent conductive hearing loss due to serous otitis media
## Central hearing loss

*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 <ref><pubmed>12795509</pubmed></ref>.
* Finally, the central hearing loss is most likely caused by poorly formed brainstem and forebrain areas which are required for auditory processing<ref><pubmed>9161611</pubmed></ref>.

|- 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. <ref><pubmed>7877418</pubmed></ref>

||
[[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. <ref><pubmed>12671419</pubmed></ref>
* 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>

[[Image:Cochlea.jpg]]

<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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{{2012Projects}}