Embryology - User contributions [en-gb]

User:Z3333865

2012-10-16T22:48:03Z

Z3333865: /* Lab Attendance */

==Lab Attendance==

Lab 1 --[[User:Z3333865|Z3333865]] 11:00, 25 July 2012 (EST)

Lab 2 --[[User:Z3333865|Z3333865]] 10:04, 1 August 2012 (EST)

Lab 3 --[[User:Z3333865|Z3333865]] 11:58, 8 August 2012 (EST)

Lab 4 --[[User:Z3333865|Z3333865]] 11:43, 15 August 2012 (EST)

Lab 5 --[[User:Z3333865|Z3333865]] 10:16, 22 August 2012 (EST)

Lab 6 --[[User:Z3333865|Z3333865]] 11:58, 29 August 2012 (EST)

Lab 7 --[[User:Z3333865|Z3333865]] 10:12, 12 September 2012 (EST)

Lab 8 --[[User:Z3333865|Z3333865]] 10:03, 19 September 2012 (EST)

Lab 9 --[[User:Z3333865|Z3333865]] 10:09, 26 September 2012 (EST)

Lab 10 --[[User:Z3333865|Z3333865]] 10:11, 3 October 2012 (EST)

Lab 11 --[[User:Z3333865|Z3333865]] 09:47, 17 October 2012 (EST) Sorry, I just realised I forgot to log in last time!

Lab 12 --[[User:Z3333865|Z3333865]] 09:47, 17 October 2012 (EST)

==Lab Exercises==

===Lab 1===

'''Question 1'''

As stated by IVF-worldwide, the history of In Vitro Fertilization (IVF) and embryo transfer (ET) dates back as early as the 1890s. Walter Heape, a professor and physician at the University of Cambridge, England, had been conducting research on reproduction in a number of animal species. He reported the first known case of embryo transplantation in rabbits, long before the applications to human fertility were even suggested. [http://www.ivf-worldwide.com/ivf-history.html IVF history]

IVF-worldwide also explains that in 1965, Robert Edwards together with Georgeanna and Howard Jones at Johns Hopkins Hospital in the USA attempted to fertilize human oocytes in vitro. The first IVF pregnancy was reported in 1973 by the Monash research team of Professors Carl Wood and John Leeton in Melbourne, Australia. Unfortunately, this resulted in early miscarriage. The first ever IVF birth occurred in Oldham, England on July 25, 1978. This birth was the result of the collaborative work of Patrick Steptoe and Robert Edwards. [http://www.ivf-worldwide.com/ivf-history.html IVF history]

Robert Edwards was awarded the 2010 Nobel Prize in Physiology or Medicine for the development of human In Vitro Fertilization (IVF) therapy. His achievements have made it possible to help treat infertility, which affects more than 1 in 10 couples worldwide. [http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/ 2010 Nobel Prize]

'''Question 2'''

<pubmed>PMC3353509</pubmed>

Traditional IVF methods involve the assisted fertilization of the oocytes with the spermatozoa. This is performed in the laboratory, whereby the physiological conditions to which the gametes are normally exposed in vivo are simulated. However, INVO (intravaginal culture of oocytes), is a simplified procedure and alternative option to conventional IVF. This assisted reproduction procedure uses the maternal vaginal cavity for incubation, instead of laboratory equipment.

Investigated in this study is the outcome of the INVO procedure and how this compares to the conventional IVF methods.
Data was obtained regarding pregnancy, live birth, and single live birth rates. Results of this study showed that the INVO procedure had comparable successful rates with traditional IVF.

''Statistics from 2008 on traditional IVF'': the pregnancy, live birth, and singleton live birth rates per oocyte retrieval were 41.6%, 33.8%, and 23%, respectively.

''Statistics from this study on INVO'': the pregnancy, live birth, and singleton live birth rates per oocyte retrieval were 40%, 31.2%, and 24%, respectively.

The study also concluded that the most significant factor determining the success rate was the age of the mother. In terms of pregnancy, live birth, and single live birth rates, a significant decrease was observed across the groups of age from ≤29 until ≥40 years old.
Results obtained by this study suggest that INVO procedures could be a viable alternative treatment for infertile patients.

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3353509/?tool=pubmed Link to paper on INVO]

===Lab 2===

====In-class exercise====

[[File: z3333865.homologous recombination and c-MYC2 expression in ES cell clones.png|thumb|500px|Confirmation of homologous recombination and c-MYC2 expression in ES cell clones.]]

'''Confirmation of homologous recombination and c-MYC2 expression in ES cell clones.'''

(A) Genomic DNA of ES cell clones 1, 14, 18 and 19 and of wildtype ES cells (wt Bruce 4) was digested with EcoRI. Digested DNA was analyzed by Southern blotting with a 5′ probe and a 3′ probe. (wt) DNA fragment of the wildtype c-Myc locus; (rec.) DNA-fragment of recombined hc-Myc locus. (B) Protein extracts were prepared of ES cell clones 1, 14, 18 and 19 as well as of wildtype ES cells (wt Bruce 4) and of a human lymphoblastoid cell line (LCL 1.11). Human c-MYC2 (hu. c-MYC, ca. 62 kDa) was detected with antibody clone Y69. In wildtype ES cells murine c-MYC2 (mu. c-MYC, ca. 64 kDa) was detected. For loading control an antibody specific for glyceraldehyde-3-phosphat-dehydrogenase (GAPDH; ca. 36 kDa) was used. Western blot results were reproduced five times.

Lehmann FM, Feicht S, Helm F, Maurberger A, Ladinig C, et al. (2012) '''Humanized c-Myc Mouse.''' PLoS ONE 7(7): e42021. doi:10.1371/journal.pone.0042021

Copyright: © 2012 Lehmann et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

====Assessment task====

[[File: z3333865.implantation.png|thumb|250px|Jam2 expression in mouse uterus during early pregnancy.]]

''Question 1''

'''Jam2 expression in mouse uterus during early pregnancy.'''

(A) In situ hybridization of Jam2 mRNA. (B) Real-time RT-PCR quantification of Jam2 mRNA. (C) JAM2 immunostaining. D1, day 1; D2, day 2; D3, day 3; D4, day 4; D4.5-I, implantation site at day 4 midnight; D4.5-NI, inter-implantation site at day 4 midnight; D5-I, implantation site on day 5; D5-NI, inter-implantation site on day 5; PD3, day 3 of pseudopregnancy; PD4, day 4 of pseudopregnancy; Arrow, embryo. Bar = 150 µm.

Su R-W, Jia B, Ni H, Lei W, Yue S-L, et al. (2012) '''Junctional Adhesion Molecule 2 Mediates the Interaction between Hatched Blastocyst and Luminal Epithelium: Induction by Progesterone and LIF.''' PLoS ONE 7(4): e34325. doi:10.1371/journal.pone.0034325

Copyright: © 2012 Su et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

''Question 2''

A protein associated with the implantation process is Hand2.

It is known that levels of this protein increase in uterine cells as progesterone levels rise. In a more recent NIH funded study, researchers discovered that Hand2 is also the switch that turns off estrogen’s stimulating effect on the epithelium.

For the study, the researchers developed a laboratory strain of mice in which the uterus fails to make Hand2. It was found that exposure to progesterone halted growth of the uterine epithelium in mice with functioning genes for Hand2. However, despite exposure to progesterone, epithelial growth continued unchecked in the mice without Hand2 genes.

Furthermore, at the time of implantation, Hand2 was expressed in uterine cells that lie beneath the surface layer of epithelial cells. Experiments have shown that estrogen stimulates the production of growth factors, which cause cells in the epithelial layer to multiply and grow. When progesterone is produced, it spurs the release of Hand2, which stops the production of growth factors. The uterine epithelial cells then stop multiplying, mature, and become receptive to the embryo. This is a key step in the process of implantation.

<pubmed>PMC3320855</pubmed>

===Lab 3===

''Question 1''

The post-fertilization age (or conceptional age) is the time that has passed since fertilization of the egg. The gestational age, however, is measured from the first day of the woman's last menstrual cycle to the current date. A normal pregnancy can range from 38 to 42 weeks.

The gestational age is approximately two weeks greater than post-fertilization age. Gestational age is more clinically significant because its start date can be clearly determined both before and after birth, whereas the exact moment of fertilization must be inferred.

[http://emedicine.medscape.com/article/259269-overview| Post-fertilization and gestational age]

''Question 2''

The somites developed from paraxial mesoderm, and will give rise to sclerotome, dermatome and myotome tissues.

The sclerotome relates to the axial skeleton and the proper functioning of the vertebral column:
Sonic hedgehog signalling causes the ventromedial portion of the somite to differentiate into sclerotome.The sclerotome then develops into cartilage (chondrocytes) due to the transcription factor Pax 1.

Dorsolaterally, the dermomyotome develops first, which then differentiates into the dorsal dermatome and the ventral myotome.

The dermatome will contribute to the formation of the dermis due to the neurotrophin 3 factor. The dermis consists of: firstly, a more superficial papillary layer which has fine collagen and elastic fibres and contains small blood vessels (arterioles and capillaries), lymph and nerves. Secondly, a deeper reticular layer with dense collagen fibres and thick elastic fibres and it contains lymph, vascular plexus, nerves and appendages.

The ventral myotome can be split up into the epaxial myotome (dorsomedial quarter) and the hypaxial myotome (dorsolateral quarter).
The epaxial myotome will result in formation of the erector spinae muscles and the hypaxial myotome will give rise to muscles of the trunk (ventrally) and limbs. The type of muscle which is formed is skeletal muscle - striated, multinucleated myofibers. Proteins such as Wnt 1 and 3 are related to the expression of genes which will cause muscle development.

Online Embryology course developed by the universities of Fribourg, Lausanne and Bern with the support of the Swiss Virtual Campus - [http://www.embryology.ch/anglais/mmuskel/skelett02.html| Somite development].

===Lab 4===

''Question 1''

One of the invasive prenatal diagnostic techniques is '''chorionic villus sampling''' (CVS). A small sample of the developing placenta is obtained to test for genetic abnormalities. To collect this sample, a slender needle is inserted through the abdomen and into the placental tissue. The chorionic villi are then examined in a laboratory. [http://www.thewomens.org.au/ChorionicVillusSamplingCVS| CVS]

Genetic abnormalities, such as Down Syndrome or Cystic Fibrosis can be tested for by this CVS diagnostic technique. It is generally performed between 10 and 12 weeks of pregnancy and has emerged as the only safe invasive prenatal diagnostic procedure prior to the 14th week of gestation.
<pubmed>16533654</pubmed>

The other invasive prenatal diagnostic technique is '''amniocentesis'''. A sample of approximately 16 mL of amniotic fluid is collected from the amniotic cavity. To collect this sample, a long needle is inserted through the abdomen and into the amniotic sac. The embryo and the placenta remain untouched during the procedure. Ultrasound is often used prior to or during the procedure to locate the amniotic sac from which the sample is taken. The test is generally performed at around 16 weeks of prenancy. [http://www.thewomens.org.au/amniocentesis| Amniocentesis procedure].

The fluid can be examined for fetal lung maturity, genetic evaluation and sex determination, the presence of infection, spina bifida and other neural-tube defects,or chromosome analysis to test for conditions such as Down syndrome. To screen for neural-tube defects and Down syndrome, blood tests can be performed. Elevated levels of the alpha feto protein may indicate a developmental abnormality. [http://www.medicinenet.com/amniocentesis/page2.htm| Amniocentesis testing]

''Question 2''

The following paper describes a therapeutic use of umbilical cord stem cells:

<pubmed>22500090</pubmed>

It has long been known that mesenchymal stem cells can contribute to the alleviation of neurologic deficits. In this paper, researchers investigated the possible mechanisms which could underly the beneficial effect of human umbilical cord-mesenchymal stem cells on spinal cord injury.

Rats used in this experiment underwent surgery to induce neuronal damage. The skin and muscles overlying the thoracic cord were separated and retracted, the T9 vertebral level was removed by laminectomy, and the underlying spinal cord segment was exposed by slitting the dural sheath. A rod was placed above T9 and dropped from a height of 25mm to induce an incomplete partial SCI. Rats were then randomly assigned to different groups. Human umbilical cord blood was obtained from normal full-term pregnant woman. The mesenchymal stem cells obtained from the human umbilical cord blood were transplanted into the boundary zone of the injured site of some rats. Rats without the transplantation were in the control group. Animals received a daily injection of bromodeoxyuridine during the 7 days after treatment. Various experiments were carried out on both the experimental and the control groups and data of both was compared.

One of the tests looked at the area of the cavity of the damaged spinal cord. Through imaging it was found that the cavity volume was smaller in the rats with transplanted mesenchymal stem cells compared to the control group.
The recovery of hindlimb function was also assessed. The motor function scores of rats with injected mesenchymal stem cells were significantly higher at 7 weeks after SCI, in comparison to the control groups. Scores demonstrated that the neurological function dramatically improved in treated rats. Thus, human umbilical cord blood-mesenchymal stem cell transplantation led to a significant improvement of behavior as well as the reduction of cavity volume after spinal cord injury.

Cells labelled with bromodeoxyuridine were counted in the ependymal and parenchymal regions. Proliferation of the newly generated cells increased greatly in treated rats as compared with the control rats. This demonstrated that the mesenchymal stem cells derived from the human umbilical cord blood could enhance proliferation of endogenous cells within the spinal cord. It was observed that both endogenous cell proliferation and oligogenesis contributed to functional recovery in the treatment group.
Rats were also examined for immunoreactivities. Results showed weak responses for the control groups, yet high responses for the treatment group. This suggests that the presence of mesenchymal stem cells creates an influential microenvironment within the spinal cord. Furthermore, transplantation of mesenchymal stem cells protected injured spinal cord cells from apoptosis.

Taken all his data together, treatment of spinal cord injuries with human umbilical cord blood-mesenchymal stem cells has a neuroregenerative and a neuroprotective effect which could be therapeutically used to treat spinal cord injuries.

===Lab 7===

''' ''Question 1a:'' ''' ''Provide a one sentence definition of a muscle satellite cell''

A muscle satellite cell is a quiescent stem cell present in muscle tissue between the sarcolema and the basal lamina of a muscle fiber, which becomes activated due to injury and allows for repair and regeneration of the muscle tissue.<ref><pubmed>12757751</pubmed></ref>

''' ''Question 1b:'' ''' ''In one paragraph, briefly discuss two examples of when satellite cells are activated''

Satellite cells are activated when muscle tissue needs to be repaired or regenerated. This is a result of injury or disease.

* Injury can be caused by various events. An example would be a bite from the Australian tiger snake, which contains the myotoxic agent notexin. <ref><pubmed>19415780</pubmed></ref> As studies have indicated, notexin causes the complete breakdown of muscle fibers and loss of functional capacity after 3 days. It was also shown that at 7 and 10 days after injection with notexin, muscles were comprised entirely of regenerating fibers.<ref><pubmed>16881061</pubmed></ref>

* Diseases can be another factor. The quickly worsening muscular disease Duchenne muscular dystrophy (DMD) is the result of a defective gene for dystrophin. Dystrophin is essential for connecting the muscle fiber cytoskeleton to the surrounding extracellular matrix.<ref><pubmed>5779432</pubmed></ref> Studies have shown that DMD results in elevated levels of satellite cells as compared to normal muscle tissue. <ref><pubmed>20467789</pubmed></ref> A mouse model of this disease was used for the first application of muscle stem cell transplantation. <ref><pubmed>2643055</pubmed></ref>

The following happens:

The quiescent satellite cells become activated and proliferate. Cells will then allign and fuse to allow for repair and/or regeneration of muscle fibers. [http://embryology.med.unsw.edu.au/embryology/images/0/02/Part_1_muscle_development_2012.pdf Injured muscle]

''' ''Question 2'' ''' ''In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury''

Spinal cord damage and other causes of long term injury affecting an innervating motor nerve will result in the partial or complete wasting away of the muscle - atrophy.<ref><pubmed>16940987</pubmed></ref> When considering both complete and incomplete injury to the spinal cord, one of the factors resulting in atrophy and a significant decrease in cross-sectional area of the muscle is the immobilisation and disuse of that tissue. <ref><pubmed>10483809</pubmed></ref> Studies have also shown that 6 weeks after the spinal cord injury took place, increased accumulation of intramuscular fat occurs in conjunction with the muscle atrophy. <ref><pubmed>15303112</pubmed></ref>

It was also noted that fast twitch type 2 muscle fibers became more numerous after complete or incomplete spinal cord injury, as compared to the slow twitch type 1 muscle fibers. <ref name="PMID9755066"><pubmed>9755066</pubmed></ref> It has been suggested that this change occurred as the muscle is no longer exercised on a long-term, consistent basis. It was also determined that in the particular study by Dupont-Versteegden ''et al.'' (1998), the affected muscle became more abundant in Myosin heavy chain type 2b. <ref name="PMID9755066"/> As a result, the muscle was more easily susceptible to fatigue.

===Lab 8===

'''Group 1'''

Firstly, the picture at the top immediately shows us the topic you are discussing: vision. This is good, but you might want to decrease the size slightly by stating the number of pixels in your file description. Your introduction includes the anatomy of the eye, which you should probably put under a separate heading. Expand the introduction a little and tell us what you will be presenting on your site.

The history is quite short – aim for more significant dates and discoveries and try to put them in an organised table. Within your history section you have images relating to development of the optic vesicle and lens. It seems like these should be incorporated in your next section on development. Good images though, but this time increase the size so the reader doesn’t have to open every single one of them to read the labels.

It seems like most work has gone into the section of development, which is good because we are focussing on the development of vision! The content relates really well and shows research has been done. There are a few sentences that strongly suggest they have been researched, however they are not references. This is in particular for the optic nerve and retina sections. Again, make sure the labels on the images can be read without having to open the file. You may also want to put the images together (optic nerve section) so the reader can easily see the changes happening during development. It is really good that you refer to the images within your text. The second half of your development section could do with a few images to complement the text. I personally think you should expand upon the lens development, because this is an important structure of the eye. What happens after migration into the embryo? If you find some related molecular information, eg. essential transcription factors, you could provide a brief explanation of these too and the role they play in vision development.

You started on your current research and a few references are present, as well as an image. I do not know what this image is and there is pretty much no text explaining any research that is currently undertaken. Please expand upon this!
The links should probably be listed under the heading ‘external links’ and as you expand upon certain sections, please keep adding to the glossary. For instance, I could not find the term ‘neuroblastic layer’ in the glossary (from the retina section).

With all of your images: please provide a title, description, source, copyright information, student image template. Some of your references will also need to be changed to avoid errors, citation of webpages and doubling-up of references. See the ‘editing basics’ on the embryology website.

'''Group 2'''

Your introduction is quite expansive and the first paragraph gives an excellent overview of what the somatosensory system actually is. At the end of the first paragraph you do refer to a picture; however, there is no picture. Please add this to show the somatosensory organisation within the body. In the second paragraph you mention some key timepoints related to the somatosensory development, which is good. After this (“Development of the system entails…lemniscal system.”) the text is probably too specific for the introduction. This can be used as an introduction for your development subheading. Please make sure that you edit the in-text references to proper references which we can access via your reference list. Also make sure you start adding terms to the glossary, eg. dorsal column-medial lemniscal system (I do not know what this means!)

You have started on your history section, but it would be more interesting and easier to read if you put this in a table. For instance: date – description – significant person. Also try to add a few more important discoveries. Again, please provide proper references. See the ‘editing basics’ section on this embryology website.

The central somatosensory differentiation is good and I can see that a lot of effort has been put into this section. The picture is very helpful and complements the text. To some extend it does seem like the sensory neurons only come from the dorsal aspect (going into the dorsal root ganglion), so maybe put a note in there that the dorsal and ventral rami are mixed nerves and both of them will contain sensory neurons that go to the dorsal root ganglion. With this image, you also have to include the student template. Text and references are good in this section and I particularly found the ‘making connections’ section very clear, organised and enjoyable to read. Do make sure that you add to the glossary – in particular terms from the ‘development of the primary cortex section’, and if possible add more images.

The touch section has a fair amount of text, but no images to complement it. This made it a bit boring to read. Make sure the subheadings stand out by making them bold. Most of the text has not been references at all, which is concerning and could potentially indicate plagiarism. I also did not read anything about the development of the various receptors (or hypotheses it no distinct evidence has been provided yet). Keep in mind we are looking at the development of the system, not the physiology. You did put in some interesting facts, such as that cell abnormalities can lead to Merkel-cell carcinoma.

Pain and hot/cold are similar to touch: good description of the physiology, but no development included. References are only provided as in-text citations or listed below, which will need to be edited to include them into the reference list. Include images to complement your text and engage the reader – this also concerns the touch section.

The pressure section has limited information regarding the development. Please include how this develops – what factors are included etc. In my opinion there is too much focus on the adult physiology. We are studying embryology… As mentioned above, please edit references and include appropriate images.

Current research looks good with an interesting image and the appropriate references, copyright and student template. The description helps to understand the image. Maybe add another research project to this section.

Add to the glossary, references and actually name the external links listed as 1) 2) and 3).

'''Group 3'''

Your introduction is quite good and gives us a brief overview of the different tastes. I also like it that you touch on the fact that it is important we recognise (via taste) food which would be dangerous to our health. In my opinion, after you mention the research (ending the sentence with …’may exist.’) you should tell the reader what you will be discussing on your page. The few lines on fatty acids does not seem to fit in, and should be part of your history section and possibly current/future research. Some specific information seems to have been researched, such as what umami codes for; however, references have not been provided. Also make sure that the image has the correct information – title, description, references, copyright, student template.

It would be more logical to put the history section next. Following this by the timeline and then go back to the cell biology, receptors and taste map etc.

The history section is good with many significant dates and clear descriptions incorporated in a table. I do see lots of numbers, which I think relate to references. I cannot find these references anywhere, so please edit this and make sure it is included in your list of references. There are also a few references listed in full in the table, so please put these down as proper references. Also, there is no good description for the year 2007 (it is mainly a reference).

The developmental timeline is expansive and very interesting! It really relates to the different developmental stages and tells us what happens over time. I hope you can include images with appropriate labels and information to this table, as it will greatly complement your text. Please do check your spelling, eg. ‘epithelium’ in week 6. Also references in this section are appropriate and are not doubled-up in the reference list. Do check reference 5 as it comes up with a cite error.

The section on cell biology and type 2 receptors is clear and easy to read. I cannot see any references though! Please be careful cause this might indicate plagiarism. The taste map is interesting and I am glad you mentioned research has indicated that the different receptors are in fact located all over the tongue – not just in particular sections. If possible, look for the original paper(s) that made this discovery.

The section on neural pathways is a little more difficult to read and I did not understand some of it. Particular terms are used in sentences which suggest little effort has been put in to explain everything in your own words. This is further indicated by the lack of references in the ‘first order neuron’ section and the majority of the ‘second order neuron’ section. I might be wrong, but then do add all your jargon to the glossary. If possible, also try to find other papers which present the same information to strengthen your points mentioned. Images for both the taste map and the cortex need referencing, copyright info, etc.

Adult tongue and taste buds. It is good you include some anatomy and physiology into your section. Do keep in mind the majority of your project should focus on embryonic development. You included the appropriate names, eg. sulcus terminalis, and I am glad to see that has also been put in the glossary. Some more terms do need to be added, eg. circumvallate. The text is good, clear and easy to read. Images are appropriate and relate to the text but need proper descriptions, citations, etc. A major let down of this section is the lack of references – please include this.

Personally, I found the abnormalities section very interesting! However, you are suddenly talking about all these genes and factors which you have not mentioned anywhere else. It might be good to provide a brief description of these in the development section or incorporate them into your developmental timeline. Images all have copyright information, but other information is missing, such as the student template and/or reference. Please check and add this.

Current research includes a lot of information. All different sections have their references which are displayed in the reference list. If you can, provide links to the website of the research groups working on current projects. Be careful not to just put your reference at the end, as you may also have to reference within the paragraph. Both pictures used will need the student template. The double tongue image will need a reference in its description too.

As mentioned before, add and edit the glossary and reference list. You should also add to the useful links (make this external links) and the image gallery, or delete these subheadings, as there is nothing there now.

'''Group 4'''

Your introduction is good and gives a brief overview of what the olfactory system entails. There were a few spelling mistakes, which can easily be corrected. Make sure you do tell the reader what you will be discussing on your page – development of the olfactory system and the particular subheadings you will focus on. The image could do with a few more labels for orientation, but besides that it complements the text and contains the correct citation, student template, etc.

The history section is good and quite extensively researched. Most groups will provide the history in a table, with dates in chronological order (to clearly show history and developing knowledge over time). This might be something to think about. I would suggest a ‘date – description – significant person’ type of format for a table. Good image, but it is displayed next to Pearson instead of Kollman. It is also difficult to see what it is and read the labels without opening the larger version, so you might want to increase its size slightly. Because this is a student image I would like to see the original – if possible provide a link to the Atlas of the Development of Man 2.
You should also explain what Kallmann’s Syndrome actually is, because this seems a little vague.

Your timeline of developmental process looks amazing and is enjoyable to read. Some of your words are printed in bold and link to the glossary. In one of your next sections the words link directly to the glossary, so you should probably do he same thing here. I really hope you can add pictures to this table to complement your text! Not quite sure what the line at the bottom (SINUSES:A:…) is doing there… either delete or expand upon this.

Structure: you only have a link here. Please provide text and image to explain the structure briefly. The YouTube link should be there to help the reader understand this section, instead of being the only thing this section is made up of. The video is not your own work, so please add your own work to this!

The normal function section was alright. It has some useful information in there, however, only a single reference listed at the end. It seemed like more references should be included within the paragraph. I would also include the fact that depolarization is an all-or-nothing response. The threshold needs to be reached for depolarization to occur, but there is no build-up over time to reach this threshold. It has to happen at that one instance. The links should be listed under the heading ‘external links’ or, if used as references, incorporated as proper references within the text. The olfactory bulb image is a little small and the description is quite brief. Though, good citation of the source and a student template is present.
I think the olfactory bulb image and the epithelium image should be included in the ‘structure’ section.

The abnormality section includes Kallmann’s syndrome and a quick definition has finally been provided! Please include this in the history section too. This section was a joy to read! Very interesting! A lot of effort has been put into the research and references have been done very well. I assume OB stands for olfactory bulb – please indicate this in the text. The dotpoints listed in the ‘clinical features’ section could do with a brief explanations instead of me having to scroll up and down between the text and the glossary. The image is excellent and shows a good simplified concept of what happens. Good descriptions, source citations, etc are added too. It was good to see diagnosis and treatment included.

Current research starts with a link, which seems quite random – include this in the external links section. You found some interesting and current research. References are only listed at the end of each paragraph, but should probably be included within as well. The image relates to one of the projects and descriptions are appropriate. Nothing has been added to the ‘role of odorant receptors’ though (apart from a reference). Please add a brief paragraph to this section.

Terms should be added to the glossary. The reference list also needs checking, because some are the same (eg. 11 & 12) and others do not have a reference (eg. 7 & 17).

'''Group 5'''

Your introduction is quite short, but it does state what you will be discussing on your page. You might want to include the normal development in the introduction, to allow for an overview of what normally happens before you actually start on the abnormal development. It just seems a little odd that you have abnormal vision as you title and then almost immediately after that you have a normal eye development heading.

I really like the chronological order used in the normal development section. It might be a bit easier to read if you use dot points. References seems to be fine, however, 4 and 5 are the same. It might also be useful to create a link to the group page on normal vision development.

Abnormal development consists of a few subheadings. Personally, I would delete the lines below the different subheadings. It will make it look more like one section on abnormal development. I think it was a good idea to look at the different parts of the eye related to abnormalities – lens, cornea, retina, etc. You look at different genes which play an important role at a certain developmental stage and you explain the resulting effects. I can see a lot of research has been done on this section. Images will need to be made bigger. They look insignificant with this size and it just seems like the text is going on and on. A lot of terms mentioned in this section are not included in the glossary, eg. Dysgenesis, substantia propria, CRX (what does it stand for?). Please add these in. Again, check your references, because some are the same, eg. 8 & 9.

Ocular manifestation is part of the abnormal development section (I think), so please make sure you show this with the headings. Again, immediately below this seems to be another heading with genetics, which has nothing included… or does LCA belong to genetics? I am a bit confused due to all your different headings and lines which seem to separate parts that may potentially belong together.

In your LCA section I would change the order of text a little: definition (as you have at the start), then epidemiology (which you have at the bottom), then the section on Dr Leber (up to “…placing great emphasis upon the high incidence of hereditary factors.”), lastly a new paragraph on the diagnosis (“As stated in the section on… diagnostic protocol for LCA”). The link to Abnormal Retinal Development does not work and will need editing. I can see that your timeline refers to LCA in particular and it is quite expansive. The one reference provided leads to a website with a timeline that seems to have been copied and pasted into your project. Please change this into your own words and (where possible) provide references to the original papers. The table also seems to be located in a strange position and it may be better to include this information in a table on history (in general), which you do not have at the moment. New research development also focuses on LCA only. Maybe create a separate section at the end where you can mention this and include more current research in brief paragraphs. The image relates well and has the appropriate citation, copyright and student template. The description could include a little more information.

Anophthalmia and microphthalmia are other genetic abnormalities described. Again, with the image you can expand slightly upon the description, but besides that it relates well to your text. Information provided is good, and includes the clinical description, genetic causes and management. Most important is that you use the same layout for your headings throughout your project. Within this one section you are using different subheadings and it all looks a bit chaotic and makes it less encouraging to read. You explain the role various genes play and I would like to know at what week/gestational stage they are important and can cause these abnormalities. Make sure all your references are correct, eg. There is no reference for 30.

It is probably good you only focused on 2 abnormalities caused by environmental factors. Images could really complement the text (although your whole page could probably use a few more images), so please add these. You include some relevant information and statistics, but make sure you also keep adding to the glossary. References are also the same for 45-48, hence these need editing.

In my opinion, firstly change the layout of your page and make it more organised with logical headings. Then focus on some of the other things mentioned above.

===Lab 9===

''' ''Question 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>22993381</pubmed>

Leptin levels are elevated in obese subjects and decreased in subjects restricted of food. This study investigates the effects of leptin concentrations on the development of the placenta and global placental gene expression profiles at d11.5.<ref name="PMID22993381"><pubmed>22993381</pubmed></ref> Pregnant mice were used and divided into 3 groups: control, mice that were undernourished and mice that were undernourished but supplemented with leptin. As stated in the study, "placentas from mothers exposed to food restriction preserved the placental labyrinth zone at the expense of the junctional zone, an effect abrogated in the restricted+ leptin group, which had a significant decrease in the labyrinth zone area compared to controls".<ref name="PMID22993381"/> Furthermore, when comparing the placentas from control and restricted+ leptin mothers there were 1128 genes which were differentially expressed. There were 281 differentially expressed genes between the control group and the restricted group.<ref name="PMID22993381"/>

This study concluded that being deprived of nutrition relates to a limited availability of energy and a decrease of the junctional zone of the placenta as mentioned above. When high levels of leptin are present, this response was altered and in fact the labyrinth zone had decreased.<ref name="PMID22993381"/>

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

Ectoderm, mesoderm and the neural crest contribute to the developing teeth.

Development of the teeth involves epithelial/mesenchymal interactions between the ectoderm of the first pharyngeal arch and cranial neural crest ectomesenchymal cells.

* The ectoderm from the first pharyngeal arch contributes to the enamel of the tooth. Some cells from the oral epithelium remain and differentiate locally into enamel-producing ameloblasts <ref name="PMID19266065"><pubmed>19266065</pubmed></ref>

* The majority of the dental papilla of the tooth has been demonstrated to be of neural crest origin. The cranial neural crest cells also give rise to various tooth cell types (odontoblasts, which produce dentine; cementoblast, which secrete cementum to cover the root dentine; osteoblasts, which participate in the formation of dental alveoli; and fibroblasts, which synthesize collagen for the periodontic ligament).<ref name="PMID19266065"/>

* During odontogenesis, non-neural crest cells have also been observed in the dental papilla region, which are mesodermally-derived migrating cells. These cells create a network of endothelial cells, contributing to the blood vessels in the pulp of the tooth.<ref><pubmed>21425080</pubmed></ref>

===Lab 11===

''Question: Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.''

<pubmed>22984641</pubmed>

The introduction of this paper outlines that retrovirus and lentivirus are generally used to produce induced pluripotent stem (iPS) cells. These integrate into the genome and allow for the expression of the specific factors needed (Yamanaka factors) to reprogram a cell to its pluripotent state. Integrating viruses do cause some concern for genome alterations. A fairly new method involves the use of the Sendai virus, which allows for a relatively efficient iPS cell conversion. It has a completely RNA-based reproductive cycle, and sustained transfection of synthetic mRNA transcripts encodes the Yamanaka factors. It has been necessary to use a feeder layer of mitotically-arrested fibroblasts when using mRNA to reprogram cells and this makes the process much more complex. It also takes approximately two weeks to induce pluripotency in human cells.

Improvements include accelerated reprogramming of cells through potentiation of the reprogramming factor cocktail delivered to the cells. This study explains a revised protocol that compresses and streamlines the mRNA reprogramming process, and which supports the rapid production of footprint-free iPSCs from human fibroblasts without the use of feeder cells or other reagents.

Various cocktails of reprogramming factors were prepared, using wild-type Oct4 or M3O. It was quickly established that more colonies were produced by using M3O-based cocktails. The results also showed that adding Nanog transcripts to the cocktail was highly beneficial, especially when M3O cocktails and Nanog were used together.
To allow for feeder-independent iPS cell derivation, data shows that it was beneficial that RNA dosing was scaled down in 24-hour transfection wells to compensate for an increase in cytotoxicity. Overall, the kinetics and efficiency were improved with this reprogramming method. It is unknown what causes the increased performance of the 24-hour regimen, but significant might be the fact that dose ramping was achieved within these wells by delivering a decreased volume of medium containing a fixed concentration of RNA. This may have increased the effective density of thinly-plated cultures. Further research into this area will be needed.

According to the authors, their work will extend the appeal of the mRNA method and bring us closer to using iPS cell technology therapeutically.

----
===References===
<references/>

User:Z3333865

2012-10-15T09:35:21Z

Z3333865: /* Lab Exercises */

==Lab Attendance==

Lab 1 --[[User:Z3333865|Z3333865]] 11:00, 25 July 2012 (EST)

Lab 2 --[[User:Z3333865|Z3333865]] 10:04, 1 August 2012 (EST)

Lab 3 --[[User:Z3333865|Z3333865]] 11:58, 8 August 2012 (EST)

Lab 4 --[[User:Z3333865|Z3333865]] 11:43, 15 August 2012 (EST)

Lab 5 --[[User:Z3333865|Z3333865]] 10:16, 22 August 2012 (EST)

Lab 6 --[[User:Z3333865|Z3333865]] 11:58, 29 August 2012 (EST)

Lab 7 --[[User:Z3333865|Z3333865]] 10:12, 12 September 2012 (EST)

Lab 8 --[[User:Z3333865|Z3333865]] 10:03, 19 September 2012 (EST)

Lab 9 --[[User:Z3333865|Z3333865]] 10:09, 26 September 2012 (EST)

Lab 10 --[[User:Z3333865|Z3333865]] 10:11, 3 October 2012 (EST)

==Lab Exercises==

===Lab 1===

'''Question 1'''

As stated by IVF-worldwide, the history of In Vitro Fertilization (IVF) and embryo transfer (ET) dates back as early as the 1890s. Walter Heape, a professor and physician at the University of Cambridge, England, had been conducting research on reproduction in a number of animal species. He reported the first known case of embryo transplantation in rabbits, long before the applications to human fertility were even suggested. [http://www.ivf-worldwide.com/ivf-history.html IVF history]

IVF-worldwide also explains that in 1965, Robert Edwards together with Georgeanna and Howard Jones at Johns Hopkins Hospital in the USA attempted to fertilize human oocytes in vitro. The first IVF pregnancy was reported in 1973 by the Monash research team of Professors Carl Wood and John Leeton in Melbourne, Australia. Unfortunately, this resulted in early miscarriage. The first ever IVF birth occurred in Oldham, England on July 25, 1978. This birth was the result of the collaborative work of Patrick Steptoe and Robert Edwards. [http://www.ivf-worldwide.com/ivf-history.html IVF history]

Robert Edwards was awarded the 2010 Nobel Prize in Physiology or Medicine for the development of human In Vitro Fertilization (IVF) therapy. His achievements have made it possible to help treat infertility, which affects more than 1 in 10 couples worldwide. [http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/ 2010 Nobel Prize]

'''Question 2'''

<pubmed>PMC3353509</pubmed>

Traditional IVF methods involve the assisted fertilization of the oocytes with the spermatozoa. This is performed in the laboratory, whereby the physiological conditions to which the gametes are normally exposed in vivo are simulated. However, INVO (intravaginal culture of oocytes), is a simplified procedure and alternative option to conventional IVF. This assisted reproduction procedure uses the maternal vaginal cavity for incubation, instead of laboratory equipment.

Investigated in this study is the outcome of the INVO procedure and how this compares to the conventional IVF methods.
Data was obtained regarding pregnancy, live birth, and single live birth rates. Results of this study showed that the INVO procedure had comparable successful rates with traditional IVF.

''Statistics from 2008 on traditional IVF'': the pregnancy, live birth, and singleton live birth rates per oocyte retrieval were 41.6%, 33.8%, and 23%, respectively.

''Statistics from this study on INVO'': the pregnancy, live birth, and singleton live birth rates per oocyte retrieval were 40%, 31.2%, and 24%, respectively.

The study also concluded that the most significant factor determining the success rate was the age of the mother. In terms of pregnancy, live birth, and single live birth rates, a significant decrease was observed across the groups of age from ≤29 until ≥40 years old.
Results obtained by this study suggest that INVO procedures could be a viable alternative treatment for infertile patients.

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3353509/?tool=pubmed Link to paper on INVO]

===Lab 2===

====In-class exercise====

[[File: z3333865.homologous recombination and c-MYC2 expression in ES cell clones.png|thumb|500px|Confirmation of homologous recombination and c-MYC2 expression in ES cell clones.]]

'''Confirmation of homologous recombination and c-MYC2 expression in ES cell clones.'''

(A) Genomic DNA of ES cell clones 1, 14, 18 and 19 and of wildtype ES cells (wt Bruce 4) was digested with EcoRI. Digested DNA was analyzed by Southern blotting with a 5′ probe and a 3′ probe. (wt) DNA fragment of the wildtype c-Myc locus; (rec.) DNA-fragment of recombined hc-Myc locus. (B) Protein extracts were prepared of ES cell clones 1, 14, 18 and 19 as well as of wildtype ES cells (wt Bruce 4) and of a human lymphoblastoid cell line (LCL 1.11). Human c-MYC2 (hu. c-MYC, ca. 62 kDa) was detected with antibody clone Y69. In wildtype ES cells murine c-MYC2 (mu. c-MYC, ca. 64 kDa) was detected. For loading control an antibody specific for glyceraldehyde-3-phosphat-dehydrogenase (GAPDH; ca. 36 kDa) was used. Western blot results were reproduced five times.

Lehmann FM, Feicht S, Helm F, Maurberger A, Ladinig C, et al. (2012) '''Humanized c-Myc Mouse.''' PLoS ONE 7(7): e42021. doi:10.1371/journal.pone.0042021

Copyright: © 2012 Lehmann et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

====Assessment task====

[[File: z3333865.implantation.png|thumb|250px|Jam2 expression in mouse uterus during early pregnancy.]]

''Question 1''

'''Jam2 expression in mouse uterus during early pregnancy.'''

(A) In situ hybridization of Jam2 mRNA. (B) Real-time RT-PCR quantification of Jam2 mRNA. (C) JAM2 immunostaining. D1, day 1; D2, day 2; D3, day 3; D4, day 4; D4.5-I, implantation site at day 4 midnight; D4.5-NI, inter-implantation site at day 4 midnight; D5-I, implantation site on day 5; D5-NI, inter-implantation site on day 5; PD3, day 3 of pseudopregnancy; PD4, day 4 of pseudopregnancy; Arrow, embryo. Bar = 150 µm.

Su R-W, Jia B, Ni H, Lei W, Yue S-L, et al. (2012) '''Junctional Adhesion Molecule 2 Mediates the Interaction between Hatched Blastocyst and Luminal Epithelium: Induction by Progesterone and LIF.''' PLoS ONE 7(4): e34325. doi:10.1371/journal.pone.0034325

Copyright: © 2012 Su et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

''Question 2''

A protein associated with the implantation process is Hand2.

It is known that levels of this protein increase in uterine cells as progesterone levels rise. In a more recent NIH funded study, researchers discovered that Hand2 is also the switch that turns off estrogen’s stimulating effect on the epithelium.

For the study, the researchers developed a laboratory strain of mice in which the uterus fails to make Hand2. It was found that exposure to progesterone halted growth of the uterine epithelium in mice with functioning genes for Hand2. However, despite exposure to progesterone, epithelial growth continued unchecked in the mice without Hand2 genes.

Furthermore, at the time of implantation, Hand2 was expressed in uterine cells that lie beneath the surface layer of epithelial cells. Experiments have shown that estrogen stimulates the production of growth factors, which cause cells in the epithelial layer to multiply and grow. When progesterone is produced, it spurs the release of Hand2, which stops the production of growth factors. The uterine epithelial cells then stop multiplying, mature, and become receptive to the embryo. This is a key step in the process of implantation.

<pubmed>PMC3320855</pubmed>

===Lab 3===

''Question 1''

The post-fertilization age (or conceptional age) is the time that has passed since fertilization of the egg. The gestational age, however, is measured from the first day of the woman's last menstrual cycle to the current date. A normal pregnancy can range from 38 to 42 weeks.

The gestational age is approximately two weeks greater than post-fertilization age. Gestational age is more clinically significant because its start date can be clearly determined both before and after birth, whereas the exact moment of fertilization must be inferred.

[http://emedicine.medscape.com/article/259269-overview| Post-fertilization and gestational age]

''Question 2''

The somites developed from paraxial mesoderm, and will give rise to sclerotome, dermatome and myotome tissues.

The sclerotome relates to the axial skeleton and the proper functioning of the vertebral column:
Sonic hedgehog signalling causes the ventromedial portion of the somite to differentiate into sclerotome.The sclerotome then develops into cartilage (chondrocytes) due to the transcription factor Pax 1.

Dorsolaterally, the dermomyotome develops first, which then differentiates into the dorsal dermatome and the ventral myotome.

The dermatome will contribute to the formation of the dermis due to the neurotrophin 3 factor. The dermis consists of: firstly, a more superficial papillary layer which has fine collagen and elastic fibres and contains small blood vessels (arterioles and capillaries), lymph and nerves. Secondly, a deeper reticular layer with dense collagen fibres and thick elastic fibres and it contains lymph, vascular plexus, nerves and appendages.

The ventral myotome can be split up into the epaxial myotome (dorsomedial quarter) and the hypaxial myotome (dorsolateral quarter).
The epaxial myotome will result in formation of the erector spinae muscles and the hypaxial myotome will give rise to muscles of the trunk (ventrally) and limbs. The type of muscle which is formed is skeletal muscle - striated, multinucleated myofibers. Proteins such as Wnt 1 and 3 are related to the expression of genes which will cause muscle development.

Online Embryology course developed by the universities of Fribourg, Lausanne and Bern with the support of the Swiss Virtual Campus - [http://www.embryology.ch/anglais/mmuskel/skelett02.html| Somite development].

===Lab 4===

''Question 1''

One of the invasive prenatal diagnostic techniques is '''chorionic villus sampling''' (CVS). A small sample of the developing placenta is obtained to test for genetic abnormalities. To collect this sample, a slender needle is inserted through the abdomen and into the placental tissue. The chorionic villi are then examined in a laboratory. [http://www.thewomens.org.au/ChorionicVillusSamplingCVS| CVS]

Genetic abnormalities, such as Down Syndrome or Cystic Fibrosis can be tested for by this CVS diagnostic technique. It is generally performed between 10 and 12 weeks of pregnancy and has emerged as the only safe invasive prenatal diagnostic procedure prior to the 14th week of gestation.
<pubmed>16533654</pubmed>

The other invasive prenatal diagnostic technique is '''amniocentesis'''. A sample of approximately 16 mL of amniotic fluid is collected from the amniotic cavity. To collect this sample, a long needle is inserted through the abdomen and into the amniotic sac. The embryo and the placenta remain untouched during the procedure. Ultrasound is often used prior to or during the procedure to locate the amniotic sac from which the sample is taken. The test is generally performed at around 16 weeks of prenancy. [http://www.thewomens.org.au/amniocentesis| Amniocentesis procedure].

The fluid can be examined for fetal lung maturity, genetic evaluation and sex determination, the presence of infection, spina bifida and other neural-tube defects,or chromosome analysis to test for conditions such as Down syndrome. To screen for neural-tube defects and Down syndrome, blood tests can be performed. Elevated levels of the alpha feto protein may indicate a developmental abnormality. [http://www.medicinenet.com/amniocentesis/page2.htm| Amniocentesis testing]

''Question 2''

The following paper describes a therapeutic use of umbilical cord stem cells:

<pubmed>22500090</pubmed>

It has long been known that mesenchymal stem cells can contribute to the alleviation of neurologic deficits. In this paper, researchers investigated the possible mechanisms which could underly the beneficial effect of human umbilical cord-mesenchymal stem cells on spinal cord injury.

Rats used in this experiment underwent surgery to induce neuronal damage. The skin and muscles overlying the thoracic cord were separated and retracted, the T9 vertebral level was removed by laminectomy, and the underlying spinal cord segment was exposed by slitting the dural sheath. A rod was placed above T9 and dropped from a height of 25mm to induce an incomplete partial SCI. Rats were then randomly assigned to different groups. Human umbilical cord blood was obtained from normal full-term pregnant woman. The mesenchymal stem cells obtained from the human umbilical cord blood were transplanted into the boundary zone of the injured site of some rats. Rats without the transplantation were in the control group. Animals received a daily injection of bromodeoxyuridine during the 7 days after treatment. Various experiments were carried out on both the experimental and the control groups and data of both was compared.

One of the tests looked at the area of the cavity of the damaged spinal cord. Through imaging it was found that the cavity volume was smaller in the rats with transplanted mesenchymal stem cells compared to the control group.
The recovery of hindlimb function was also assessed. The motor function scores of rats with injected mesenchymal stem cells were significantly higher at 7 weeks after SCI, in comparison to the control groups. Scores demonstrated that the neurological function dramatically improved in treated rats. Thus, human umbilical cord blood-mesenchymal stem cell transplantation led to a significant improvement of behavior as well as the reduction of cavity volume after spinal cord injury.

Cells labelled with bromodeoxyuridine were counted in the ependymal and parenchymal regions. Proliferation of the newly generated cells increased greatly in treated rats as compared with the control rats. This demonstrated that the mesenchymal stem cells derived from the human umbilical cord blood could enhance proliferation of endogenous cells within the spinal cord. It was observed that both endogenous cell proliferation and oligogenesis contributed to functional recovery in the treatment group.
Rats were also examined for immunoreactivities. Results showed weak responses for the control groups, yet high responses for the treatment group. This suggests that the presence of mesenchymal stem cells creates an influential microenvironment within the spinal cord. Furthermore, transplantation of mesenchymal stem cells protected injured spinal cord cells from apoptosis.

Taken all his data together, treatment of spinal cord injuries with human umbilical cord blood-mesenchymal stem cells has a neuroregenerative and a neuroprotective effect which could be therapeutically used to treat spinal cord injuries.

===Lab 7===

''' ''Question 1a:'' ''' ''Provide a one sentence definition of a muscle satellite cell''

A muscle satellite cell is a quiescent stem cell present in muscle tissue between the sarcolema and the basal lamina of a muscle fiber, which becomes activated due to injury and allows for repair and regeneration of the muscle tissue.<ref><pubmed>12757751</pubmed></ref>

''' ''Question 1b:'' ''' ''In one paragraph, briefly discuss two examples of when satellite cells are activated''

Satellite cells are activated when muscle tissue needs to be repaired or regenerated. This is a result of injury or disease.

* Injury can be caused by various events. An example would be a bite from the Australian tiger snake, which contains the myotoxic agent notexin. <ref><pubmed>19415780</pubmed></ref> As studies have indicated, notexin causes the complete breakdown of muscle fibers and loss of functional capacity after 3 days. It was also shown that at 7 and 10 days after injection with notexin, muscles were comprised entirely of regenerating fibers.<ref><pubmed>16881061</pubmed></ref>

* Diseases can be another factor. The quickly worsening muscular disease Duchenne muscular dystrophy (DMD) is the result of a defective gene for dystrophin. Dystrophin is essential for connecting the muscle fiber cytoskeleton to the surrounding extracellular matrix.<ref><pubmed>5779432</pubmed></ref> Studies have shown that DMD results in elevated levels of satellite cells as compared to normal muscle tissue. <ref><pubmed>20467789</pubmed></ref> A mouse model of this disease was used for the first application of muscle stem cell transplantation. <ref><pubmed>2643055</pubmed></ref>

The following happens:

The quiescent satellite cells become activated and proliferate. Cells will then allign and fuse to allow for repair and/or regeneration of muscle fibers. [http://embryology.med.unsw.edu.au/embryology/images/0/02/Part_1_muscle_development_2012.pdf Injured muscle]

''' ''Question 2'' ''' ''In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury''

Spinal cord damage and other causes of long term injury affecting an innervating motor nerve will result in the partial or complete wasting away of the muscle - atrophy.<ref><pubmed>16940987</pubmed></ref> When considering both complete and incomplete injury to the spinal cord, one of the factors resulting in atrophy and a significant decrease in cross-sectional area of the muscle is the immobilisation and disuse of that tissue. <ref><pubmed>10483809</pubmed></ref> Studies have also shown that 6 weeks after the spinal cord injury took place, increased accumulation of intramuscular fat occurs in conjunction with the muscle atrophy. <ref><pubmed>15303112</pubmed></ref>

It was also noted that fast twitch type 2 muscle fibers became more numerous after complete or incomplete spinal cord injury, as compared to the slow twitch type 1 muscle fibers. <ref name="PMID9755066"><pubmed>9755066</pubmed></ref> It has been suggested that this change occurred as the muscle is no longer exercised on a long-term, consistent basis. It was also determined that in the particular study by Dupont-Versteegden ''et al.'' (1998), the affected muscle became more abundant in Myosin heavy chain type 2b. <ref name="PMID9755066"/> As a result, the muscle was more easily susceptible to fatigue.

===Lab 8===

'''Group 1'''

Firstly, the picture at the top immediately shows us the topic you are discussing: vision. This is good, but you might want to decrease the size slightly by stating the number of pixels in your file description. Your introduction includes the anatomy of the eye, which you should probably put under a separate heading. Expand the introduction a little and tell us what you will be presenting on your site.

The history is quite short – aim for more significant dates and discoveries and try to put them in an organised table. Within your history section you have images relating to development of the optic vesicle and lens. It seems like these should be incorporated in your next section on development. Good images though, but this time increase the size so the reader doesn’t have to open every single one of them to read the labels.

It seems like most work has gone into the section of development, which is good because we are focussing on the development of vision! The content relates really well and shows research has been done. There are a few sentences that strongly suggest they have been researched, however they are not references. This is in particular for the optic nerve and retina sections. Again, make sure the labels on the images can be read without having to open the file. You may also want to put the images together (optic nerve section) so the reader can easily see the changes happening during development. It is really good that you refer to the images within your text. The second half of your development section could do with a few images to complement the text. I personally think you should expand upon the lens development, because this is an important structure of the eye. What happens after migration into the embryo? If you find some related molecular information, eg. essential transcription factors, you could provide a brief explanation of these too and the role they play in vision development.

You started on your current research and a few references are present, as well as an image. I do not know what this image is and there is pretty much no text explaining any research that is currently undertaken. Please expand upon this!
The links should probably be listed under the heading ‘external links’ and as you expand upon certain sections, please keep adding to the glossary. For instance, I could not find the term ‘neuroblastic layer’ in the glossary (from the retina section).

With all of your images: please provide a title, description, source, copyright information, student image template. Some of your references will also need to be changed to avoid errors, citation of webpages and doubling-up of references. See the ‘editing basics’ on the embryology website.

'''Group 2'''

Your introduction is quite expansive and the first paragraph gives an excellent overview of what the somatosensory system actually is. At the end of the first paragraph you do refer to a picture; however, there is no picture. Please add this to show the somatosensory organisation within the body. In the second paragraph you mention some key timepoints related to the somatosensory development, which is good. After this (“Development of the system entails…lemniscal system.”) the text is probably too specific for the introduction. This can be used as an introduction for your development subheading. Please make sure that you edit the in-text references to proper references which we can access via your reference list. Also make sure you start adding terms to the glossary, eg. dorsal column-medial lemniscal system (I do not know what this means!)

You have started on your history section, but it would be more interesting and easier to read if you put this in a table. For instance: date – description – significant person. Also try to add a few more important discoveries. Again, please provide proper references. See the ‘editing basics’ section on this embryology website.

The central somatosensory differentiation is good and I can see that a lot of effort has been put into this section. The picture is very helpful and complements the text. To some extend it does seem like the sensory neurons only come from the dorsal aspect (going into the dorsal root ganglion), so maybe put a note in there that the dorsal and ventral rami are mixed nerves and both of them will contain sensory neurons that go to the dorsal root ganglion. With this image, you also have to include the student template. Text and references are good in this section and I particularly found the ‘making connections’ section very clear, organised and enjoyable to read. Do make sure that you add to the glossary – in particular terms from the ‘development of the primary cortex section’, and if possible add more images.

The touch section has a fair amount of text, but no images to complement it. This made it a bit boring to read. Make sure the subheadings stand out by making them bold. Most of the text has not been references at all, which is concerning and could potentially indicate plagiarism. I also did not read anything about the development of the various receptors (or hypotheses it no distinct evidence has been provided yet). Keep in mind we are looking at the development of the system, not the physiology. You did put in some interesting facts, such as that cell abnormalities can lead to Merkel-cell carcinoma.

Pain and hot/cold are similar to touch: good description of the physiology, but no development included. References are only provided as in-text citations or listed below, which will need to be edited to include them into the reference list. Include images to complement your text and engage the reader – this also concerns the touch section.

The pressure section has limited information regarding the development. Please include how this develops – what factors are included etc. In my opinion there is too much focus on the adult physiology. We are studying embryology… As mentioned above, please edit references and include appropriate images.

Current research looks good with an interesting image and the appropriate references, copyright and student template. The description helps to understand the image. Maybe add another research project to this section.

Add to the glossary, references and actually name the external links listed as 1) 2) and 3).

'''Group 3'''

Your introduction is quite good and gives us a brief overview of the different tastes. I also like it that you touch on the fact that it is important we recognise (via taste) food which would be dangerous to our health. In my opinion, after you mention the research (ending the sentence with …’may exist.’) you should tell the reader what you will be discussing on your page. The few lines on fatty acids does not seem to fit in, and should be part of your history section and possibly current/future research. Some specific information seems to have been researched, such as what umami codes for; however, references have not been provided. Also make sure that the image has the correct information – title, description, references, copyright, student template.

It would be more logical to put the history section next. Following this by the timeline and then go back to the cell biology, receptors and taste map etc.

The history section is good with many significant dates and clear descriptions incorporated in a table. I do see lots of numbers, which I think relate to references. I cannot find these references anywhere, so please edit this and make sure it is included in your list of references. There are also a few references listed in full in the table, so please put these down as proper references. Also, there is no good description for the year 2007 (it is mainly a reference).

The developmental timeline is expansive and very interesting! It really relates to the different developmental stages and tells us what happens over time. I hope you can include images with appropriate labels and information to this table, as it will greatly complement your text. Please do check your spelling, eg. ‘epithelium’ in week 6. Also references in this section are appropriate and are not doubled-up in the reference list. Do check reference 5 as it comes up with a cite error.

The section on cell biology and type 2 receptors is clear and easy to read. I cannot see any references though! Please be careful cause this might indicate plagiarism. The taste map is interesting and I am glad you mentioned research has indicated that the different receptors are in fact located all over the tongue – not just in particular sections. If possible, look for the original paper(s) that made this discovery.

The section on neural pathways is a little more difficult to read and I did not understand some of it. Particular terms are used in sentences which suggest little effort has been put in to explain everything in your own words. This is further indicated by the lack of references in the ‘first order neuron’ section and the majority of the ‘second order neuron’ section. I might be wrong, but then do add all your jargon to the glossary. If possible, also try to find other papers which present the same information to strengthen your points mentioned. Images for both the taste map and the cortex need referencing, copyright info, etc.

Adult tongue and taste buds. It is good you include some anatomy and physiology into your section. Do keep in mind the majority of your project should focus on embryonic development. You included the appropriate names, eg. sulcus terminalis, and I am glad to see that has also been put in the glossary. Some more terms do need to be added, eg. circumvallate. The text is good, clear and easy to read. Images are appropriate and relate to the text but need proper descriptions, citations, etc. A major let down of this section is the lack of references – please include this.

Personally, I found the abnormalities section very interesting! However, you are suddenly talking about all these genes and factors which you have not mentioned anywhere else. It might be good to provide a brief description of these in the development section or incorporate them into your developmental timeline. Images all have copyright information, but other information is missing, such as the student template and/or reference. Please check and add this.

Current research includes a lot of information. All different sections have their references which are displayed in the reference list. If you can, provide links to the website of the research groups working on current projects. Be careful not to just put your reference at the end, as you may also have to reference within the paragraph. Both pictures used will need the student template. The double tongue image will need a reference in its description too.

As mentioned before, add and edit the glossary and reference list. You should also add to the useful links (make this external links) and the image gallery, or delete these subheadings, as there is nothing there now.

'''Group 4'''

Your introduction is good and gives a brief overview of what the olfactory system entails. There were a few spelling mistakes, which can easily be corrected. Make sure you do tell the reader what you will be discussing on your page – development of the olfactory system and the particular subheadings you will focus on. The image could do with a few more labels for orientation, but besides that it complements the text and contains the correct citation, student template, etc.

The history section is good and quite extensively researched. Most groups will provide the history in a table, with dates in chronological order (to clearly show history and developing knowledge over time). This might be something to think about. I would suggest a ‘date – description – significant person’ type of format for a table. Good image, but it is displayed next to Pearson instead of Kollman. It is also difficult to see what it is and read the labels without opening the larger version, so you might want to increase its size slightly. Because this is a student image I would like to see the original – if possible provide a link to the Atlas of the Development of Man 2.
You should also explain what Kallmann’s Syndrome actually is, because this seems a little vague.

Your timeline of developmental process looks amazing and is enjoyable to read. Some of your words are printed in bold and link to the glossary. In one of your next sections the words link directly to the glossary, so you should probably do he same thing here. I really hope you can add pictures to this table to complement your text! Not quite sure what the line at the bottom (SINUSES:A:…) is doing there… either delete or expand upon this.

Structure: you only have a link here. Please provide text and image to explain the structure briefly. The YouTube link should be there to help the reader understand this section, instead of being the only thing this section is made up of. The video is not your own work, so please add your own work to this!

The normal function section was alright. It has some useful information in there, however, only a single reference listed at the end. It seemed like more references should be included within the paragraph. I would also include the fact that depolarization is an all-or-nothing response. The threshold needs to be reached for depolarization to occur, but there is no build-up over time to reach this threshold. It has to happen at that one instance. The links should be listed under the heading ‘external links’ or, if used as references, incorporated as proper references within the text. The olfactory bulb image is a little small and the description is quite brief. Though, good citation of the source and a student template is present.
I think the olfactory bulb image and the epithelium image should be included in the ‘structure’ section.

The abnormality section includes Kallmann’s syndrome and a quick definition has finally been provided! Please include this in the history section too. This section was a joy to read! Very interesting! A lot of effort has been put into the research and references have been done very well. I assume OB stands for olfactory bulb – please indicate this in the text. The dotpoints listed in the ‘clinical features’ section could do with a brief explanations instead of me having to scroll up and down between the text and the glossary. The image is excellent and shows a good simplified concept of what happens. Good descriptions, source citations, etc are added too. It was good to see diagnosis and treatment included.

Current research starts with a link, which seems quite random – include this in the external links section. You found some interesting and current research. References are only listed at the end of each paragraph, but should probably be included within as well. The image relates to one of the projects and descriptions are appropriate. Nothing has been added to the ‘role of odorant receptors’ though (apart from a reference). Please add a brief paragraph to this section.

Terms should be added to the glossary. The reference list also needs checking, because some are the same (eg. 11 & 12) and others do not have a reference (eg. 7 & 17).

'''Group 5'''

Your introduction is quite short, but it does state what you will be discussing on your page. You might want to include the normal development in the introduction, to allow for an overview of what normally happens before you actually start on the abnormal development. It just seems a little odd that you have abnormal vision as you title and then almost immediately after that you have a normal eye development heading.

I really like the chronological order used in the normal development section. It might be a bit easier to read if you use dot points. References seems to be fine, however, 4 and 5 are the same. It might also be useful to create a link to the group page on normal vision development.

Abnormal development consists of a few subheadings. Personally, I would delete the lines below the different subheadings. It will make it look more like one section on abnormal development. I think it was a good idea to look at the different parts of the eye related to abnormalities – lens, cornea, retina, etc. You look at different genes which play an important role at a certain developmental stage and you explain the resulting effects. I can see a lot of research has been done on this section. Images will need to be made bigger. They look insignificant with this size and it just seems like the text is going on and on. A lot of terms mentioned in this section are not included in the glossary, eg. Dysgenesis, substantia propria, CRX (what does it stand for?). Please add these in. Again, check your references, because some are the same, eg. 8 & 9.

Ocular manifestation is part of the abnormal development section (I think), so please make sure you show this with the headings. Again, immediately below this seems to be another heading with genetics, which has nothing included… or does LCA belong to genetics? I am a bit confused due to all your different headings and lines which seem to separate parts that may potentially belong together.

In your LCA section I would change the order of text a little: definition (as you have at the start), then epidemiology (which you have at the bottom), then the section on Dr Leber (up to “…placing great emphasis upon the high incidence of hereditary factors.”), lastly a new paragraph on the diagnosis (“As stated in the section on… diagnostic protocol for LCA”). The link to Abnormal Retinal Development does not work and will need editing. I can see that your timeline refers to LCA in particular and it is quite expansive. The one reference provided leads to a website with a timeline that seems to have been copied and pasted into your project. Please change this into your own words and (where possible) provide references to the original papers. The table also seems to be located in a strange position and it may be better to include this information in a table on history (in general), which you do not have at the moment. New research development also focuses on LCA only. Maybe create a separate section at the end where you can mention this and include more current research in brief paragraphs. The image relates well and has the appropriate citation, copyright and student template. The description could include a little more information.

Anophthalmia and microphthalmia are other genetic abnormalities described. Again, with the image you can expand slightly upon the description, but besides that it relates well to your text. Information provided is good, and includes the clinical description, genetic causes and management. Most important is that you use the same layout for your headings throughout your project. Within this one section you are using different subheadings and it all looks a bit chaotic and makes it less encouraging to read. You explain the role various genes play and I would like to know at what week/gestational stage they are important and can cause these abnormalities. Make sure all your references are correct, eg. There is no reference for 30.

It is probably good you only focused on 2 abnormalities caused by environmental factors. Images could really complement the text (although your whole page could probably use a few more images), so please add these. You include some relevant information and statistics, but make sure you also keep adding to the glossary. References are also the same for 45-48, hence these need editing.

In my opinion, firstly change the layout of your page and make it more organised with logical headings. Then focus on some of the other things mentioned above.

===Lab 9===

''' ''Question 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>22993381</pubmed>

Leptin levels are elevated in obese subjects and decreased in subjects restricted of food. This study investigates the effects of leptin concentrations on the development of the placenta and global placental gene expression profiles at d11.5.<ref name="PMID22993381"><pubmed>22993381</pubmed></ref> Pregnant mice were used and divided into 3 groups: control, mice that were undernourished and mice that were undernourished but supplemented with leptin. As stated in the study, "placentas from mothers exposed to food restriction preserved the placental labyrinth zone at the expense of the junctional zone, an effect abrogated in the restricted+ leptin group, which had a significant decrease in the labyrinth zone area compared to controls".<ref name="PMID22993381"/> Furthermore, when comparing the placentas from control and restricted+ leptin mothers there were 1128 genes which were differentially expressed. There were 281 differentially expressed genes between the control group and the restricted group.<ref name="PMID22993381"/>

This study concluded that being deprived of nutrition relates to a limited availability of energy and a decrease of the junctional zone of the placenta as mentioned above. When high levels of leptin are present, this response was altered and in fact the labyrinth zone had decreased.<ref name="PMID22993381"/>

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

Ectoderm, mesoderm and the neural crest contribute to the developing teeth.

Development of the teeth involves epithelial/mesenchymal interactions between the ectoderm of the first pharyngeal arch and cranial neural crest ectomesenchymal cells.

* The ectoderm from the first pharyngeal arch contributes to the enamel of the tooth. Some cells from the oral epithelium remain and differentiate locally into enamel-producing ameloblasts <ref name="PMID19266065"><pubmed>19266065</pubmed></ref>

* The majority of the dental papilla of the tooth has been demonstrated to be of neural crest origin. The cranial neural crest cells also give rise to various tooth cell types (odontoblasts, which produce dentine; cementoblast, which secrete cementum to cover the root dentine; osteoblasts, which participate in the formation of dental alveoli; and fibroblasts, which synthesize collagen for the periodontic ligament).<ref name="PMID19266065"/>

* During odontogenesis, non-neural crest cells have also been observed in the dental papilla region, which are mesodermally-derived migrating cells. These cells create a network of endothelial cells, contributing to the blood vessels in the pulp of the tooth.<ref><pubmed>21425080</pubmed></ref>

===Lab 11===

''Question: Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.''

<pubmed>22984641</pubmed>

The introduction of this paper outlines that retrovirus and lentivirus are generally used to produce induced pluripotent stem (iPS) cells. These integrate into the genome and allow for the expression of the specific factors needed (Yamanaka factors) to reprogram a cell to its pluripotent state. Integrating viruses do cause some concern for genome alterations. A fairly new method involves the use of the Sendai virus, which allows for a relatively efficient iPS cell conversion. It has a completely RNA-based reproductive cycle, and sustained transfection of synthetic mRNA transcripts encodes the Yamanaka factors. It has been necessary to use a feeder layer of mitotically-arrested fibroblasts when using mRNA to reprogram cells and this makes the process much more complex. It also takes approximately two weeks to induce pluripotency in human cells.

Improvements include accelerated reprogramming of cells through potentiation of the reprogramming factor cocktail delivered to the cells. This study explains a revised protocol that compresses and streamlines the mRNA reprogramming process, and which supports the rapid production of footprint-free iPSCs from human fibroblasts without the use of feeder cells or other reagents.

Various cocktails of reprogramming factors were prepared, using wild-type Oct4 or M3O. It was quickly established that more colonies were produced by using M3O-based cocktails. The results also showed that adding Nanog transcripts to the cocktail was highly beneficial, especially when M3O cocktails and Nanog were used together.
To allow for feeder-independent iPS cell derivation, data shows that it was beneficial that RNA dosing was scaled down in 24-hour transfection wells to compensate for an increase in cytotoxicity. Overall, the kinetics and efficiency were improved with this reprogramming method. It is unknown what causes the increased performance of the 24-hour regimen, but significant might be the fact that dose ramping was achieved within these wells by delivering a decreased volume of medium containing a fixed concentration of RNA. This may have increased the effective density of thinly-plated cultures. Further research into this area will be needed.

According to the authors, their work will extend the appeal of the mRNA method and bring us closer to using iPS cell technology therapeutically.

----
===References===
<references/>

User:Z3333865

2012-10-15T03:51:43Z

Z3333865: /* Lab Exercises */

==Lab Attendance==

Lab 1 --[[User:Z3333865|Z3333865]] 11:00, 25 July 2012 (EST)

Lab 2 --[[User:Z3333865|Z3333865]] 10:04, 1 August 2012 (EST)

Lab 3 --[[User:Z3333865|Z3333865]] 11:58, 8 August 2012 (EST)

Lab 4 --[[User:Z3333865|Z3333865]] 11:43, 15 August 2012 (EST)

Lab 5 --[[User:Z3333865|Z3333865]] 10:16, 22 August 2012 (EST)

Lab 6 --[[User:Z3333865|Z3333865]] 11:58, 29 August 2012 (EST)

Lab 7 --[[User:Z3333865|Z3333865]] 10:12, 12 September 2012 (EST)

Lab 8 --[[User:Z3333865|Z3333865]] 10:03, 19 September 2012 (EST)

Lab 9 --[[User:Z3333865|Z3333865]] 10:09, 26 September 2012 (EST)

Lab 10 --[[User:Z3333865|Z3333865]] 10:11, 3 October 2012 (EST)

==Lab Exercises==

===Lab 1===

'''Question 1'''

As stated by IVF-worldwide, the history of In Vitro Fertilization (IVF) and embryo transfer (ET) dates back as early as the 1890s. Walter Heape, a professor and physician at the University of Cambridge, England, had been conducting research on reproduction in a number of animal species. He reported the first known case of embryo transplantation in rabbits, long before the applications to human fertility were even suggested. [http://www.ivf-worldwide.com/ivf-history.html IVF history]

IVF-worldwide also explains that in 1965, Robert Edwards together with Georgeanna and Howard Jones at Johns Hopkins Hospital in the USA attempted to fertilize human oocytes in vitro. The first IVF pregnancy was reported in 1973 by the Monash research team of Professors Carl Wood and John Leeton in Melbourne, Australia. Unfortunately, this resulted in early miscarriage. The first ever IVF birth occurred in Oldham, England on July 25, 1978. This birth was the result of the collaborative work of Patrick Steptoe and Robert Edwards. [http://www.ivf-worldwide.com/ivf-history.html IVF history]

Robert Edwards was awarded the 2010 Nobel Prize in Physiology or Medicine for the development of human In Vitro Fertilization (IVF) therapy. His achievements have made it possible to help treat infertility, which affects more than 1 in 10 couples worldwide. [http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/ 2010 Nobel Prize]

'''Question 2'''

<pubmed>PMC3353509</pubmed>

Traditional IVF methods involve the assisted fertilization of the oocytes with the spermatozoa. This is performed in the laboratory, whereby the physiological conditions to which the gametes are normally exposed in vivo are simulated. However, INVO (intravaginal culture of oocytes), is a simplified procedure and alternative option to conventional IVF. This assisted reproduction procedure uses the maternal vaginal cavity for incubation, instead of laboratory equipment.

Investigated in this study is the outcome of the INVO procedure and how this compares to the conventional IVF methods.
Data was obtained regarding pregnancy, live birth, and single live birth rates. Results of this study showed that the INVO procedure had comparable successful rates with traditional IVF.

''Statistics from 2008 on traditional IVF'': the pregnancy, live birth, and singleton live birth rates per oocyte retrieval were 41.6%, 33.8%, and 23%, respectively.

''Statistics from this study on INVO'': the pregnancy, live birth, and singleton live birth rates per oocyte retrieval were 40%, 31.2%, and 24%, respectively.

The study also concluded that the most significant factor determining the success rate was the age of the mother. In terms of pregnancy, live birth, and single live birth rates, a significant decrease was observed across the groups of age from ≤29 until ≥40 years old.
Results obtained by this study suggest that INVO procedures could be a viable alternative treatment for infertile patients.

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3353509/?tool=pubmed Link to paper on INVO]

===Lab 2===

====In-class exercise====

[[File: z3333865.homologous recombination and c-MYC2 expression in ES cell clones.png|thumb|500px|Confirmation of homologous recombination and c-MYC2 expression in ES cell clones.]]

'''Confirmation of homologous recombination and c-MYC2 expression in ES cell clones.'''

(A) Genomic DNA of ES cell clones 1, 14, 18 and 19 and of wildtype ES cells (wt Bruce 4) was digested with EcoRI. Digested DNA was analyzed by Southern blotting with a 5′ probe and a 3′ probe. (wt) DNA fragment of the wildtype c-Myc locus; (rec.) DNA-fragment of recombined hc-Myc locus. (B) Protein extracts were prepared of ES cell clones 1, 14, 18 and 19 as well as of wildtype ES cells (wt Bruce 4) and of a human lymphoblastoid cell line (LCL 1.11). Human c-MYC2 (hu. c-MYC, ca. 62 kDa) was detected with antibody clone Y69. In wildtype ES cells murine c-MYC2 (mu. c-MYC, ca. 64 kDa) was detected. For loading control an antibody specific for glyceraldehyde-3-phosphat-dehydrogenase (GAPDH; ca. 36 kDa) was used. Western blot results were reproduced five times.

Lehmann FM, Feicht S, Helm F, Maurberger A, Ladinig C, et al. (2012) '''Humanized c-Myc Mouse.''' PLoS ONE 7(7): e42021. doi:10.1371/journal.pone.0042021

Copyright: © 2012 Lehmann et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

====Assessment task====

[[File: z3333865.implantation.png|thumb|250px|Jam2 expression in mouse uterus during early pregnancy.]]

''Question 1''

'''Jam2 expression in mouse uterus during early pregnancy.'''

(A) In situ hybridization of Jam2 mRNA. (B) Real-time RT-PCR quantification of Jam2 mRNA. (C) JAM2 immunostaining. D1, day 1; D2, day 2; D3, day 3; D4, day 4; D4.5-I, implantation site at day 4 midnight; D4.5-NI, inter-implantation site at day 4 midnight; D5-I, implantation site on day 5; D5-NI, inter-implantation site on day 5; PD3, day 3 of pseudopregnancy; PD4, day 4 of pseudopregnancy; Arrow, embryo. Bar = 150 µm.

Su R-W, Jia B, Ni H, Lei W, Yue S-L, et al. (2012) '''Junctional Adhesion Molecule 2 Mediates the Interaction between Hatched Blastocyst and Luminal Epithelium: Induction by Progesterone and LIF.''' PLoS ONE 7(4): e34325. doi:10.1371/journal.pone.0034325

Copyright: © 2012 Su et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

''Question 2''

A protein associated with the implantation process is Hand2.

It is known that levels of this protein increase in uterine cells as progesterone levels rise. In a more recent NIH funded study, researchers discovered that Hand2 is also the switch that turns off estrogen’s stimulating effect on the epithelium.

For the study, the researchers developed a laboratory strain of mice in which the uterus fails to make Hand2. It was found that exposure to progesterone halted growth of the uterine epithelium in mice with functioning genes for Hand2. However, despite exposure to progesterone, epithelial growth continued unchecked in the mice without Hand2 genes.

Furthermore, at the time of implantation, Hand2 was expressed in uterine cells that lie beneath the surface layer of epithelial cells. Experiments have shown that estrogen stimulates the production of growth factors, which cause cells in the epithelial layer to multiply and grow. When progesterone is produced, it spurs the release of Hand2, which stops the production of growth factors. The uterine epithelial cells then stop multiplying, mature, and become receptive to the embryo. This is a key step in the process of implantation.

<pubmed>PMC3320855</pubmed>

===Lab 3===

''Question 1''

The post-fertilization age (or conceptional age) is the time that has passed since fertilization of the egg. The gestational age, however, is measured from the first day of the woman's last menstrual cycle to the current date. A normal pregnancy can range from 38 to 42 weeks.

The gestational age is approximately two weeks greater than post-fertilization age. Gestational age is more clinically significant because its start date can be clearly determined both before and after birth, whereas the exact moment of fertilization must be inferred.

[http://emedicine.medscape.com/article/259269-overview| Post-fertilization and gestational age]

''Question 2''

The somites developed from paraxial mesoderm, and will give rise to sclerotome, dermatome and myotome tissues.

The sclerotome relates to the axial skeleton and the proper functioning of the vertebral column:
Sonic hedgehog signalling causes the ventromedial portion of the somite to differentiate into sclerotome.The sclerotome then develops into cartilage (chondrocytes) due to the transcription factor Pax 1.

Dorsolaterally, the dermomyotome develops first, which then differentiates into the dorsal dermatome and the ventral myotome.

The dermatome will contribute to the formation of the dermis due to the neurotrophin 3 factor. The dermis consists of: firstly, a more superficial papillary layer which has fine collagen and elastic fibres and contains small blood vessels (arterioles and capillaries), lymph and nerves. Secondly, a deeper reticular layer with dense collagen fibres and thick elastic fibres and it contains lymph, vascular plexus, nerves and appendages.

The ventral myotome can be split up into the epaxial myotome (dorsomedial quarter) and the hypaxial myotome (dorsolateral quarter).
The epaxial myotome will result in formation of the erector spinae muscles and the hypaxial myotome will give rise to muscles of the trunk (ventrally) and limbs. The type of muscle which is formed is skeletal muscle - striated, multinucleated myofibers. Proteins such as Wnt 1 and 3 are related to the expression of genes which will cause muscle development.

Online Embryology course developed by the universities of Fribourg, Lausanne and Bern with the support of the Swiss Virtual Campus - [http://www.embryology.ch/anglais/mmuskel/skelett02.html| Somite development].

===Lab 4===

''Question 1''

One of the invasive prenatal diagnostic techniques is '''chorionic villus sampling''' (CVS). A small sample of the developing placenta is obtained to test for genetic abnormalities. To collect this sample, a slender needle is inserted through the abdomen and into the placental tissue. The chorionic villi are then examined in a laboratory. [http://www.thewomens.org.au/ChorionicVillusSamplingCVS| CVS]

Genetic abnormalities, such as Down Syndrome or Cystic Fibrosis can be tested for by this CVS diagnostic technique. It is generally performed between 10 and 12 weeks of pregnancy and has emerged as the only safe invasive prenatal diagnostic procedure prior to the 14th week of gestation.
<pubmed>16533654</pubmed>

The other invasive prenatal diagnostic technique is '''amniocentesis'''. A sample of approximately 16 mL of amniotic fluid is collected from the amniotic cavity. To collect this sample, a long needle is inserted through the abdomen and into the amniotic sac. The embryo and the placenta remain untouched during the procedure. Ultrasound is often used prior to or during the procedure to locate the amniotic sac from which the sample is taken. The test is generally performed at around 16 weeks of prenancy. [http://www.thewomens.org.au/amniocentesis| Amniocentesis procedure].

The fluid can be examined for fetal lung maturity, genetic evaluation and sex determination, the presence of infection, spina bifida and other neural-tube defects,or chromosome analysis to test for conditions such as Down syndrome. To screen for neural-tube defects and Down syndrome, blood tests can be performed. Elevated levels of the alpha feto protein may indicate a developmental abnormality. [http://www.medicinenet.com/amniocentesis/page2.htm| Amniocentesis testing]

''Question 2''

The following paper describes a therapeutic use of umbilical cord stem cells:

<pubmed>22500090</pubmed>

It has long been known that mesenchymal stem cells can contribute to the alleviation of neurologic deficits. In this paper, researchers investigated the possible mechanisms which could underly the beneficial effect of human umbilical cord-mesenchymal stem cells on spinal cord injury.

Rats used in this experiment underwent surgery to induce neuronal damage. The skin and muscles overlying the thoracic cord were separated and retracted, the T9 vertebral level was removed by laminectomy, and the underlying spinal cord segment was exposed by slitting the dural sheath. A rod was placed above T9 and dropped from a height of 25mm to induce an incomplete partial SCI. Rats were then randomly assigned to different groups. Human umbilical cord blood was obtained from normal full-term pregnant woman. The mesenchymal stem cells obtained from the human umbilical cord blood were transplanted into the boundary zone of the injured site of some rats. Rats without the transplantation were in the control group. Animals received a daily injection of bromodeoxyuridine during the 7 days after treatment. Various experiments were carried out on both the experimental and the control groups and data of both was compared.

One of the tests looked at the area of the cavity of the damaged spinal cord. Through imaging it was found that the cavity volume was smaller in the rats with transplanted mesenchymal stem cells compared to the control group.
The recovery of hindlimb function was also assessed. The motor function scores of rats with injected mesenchymal stem cells were significantly higher at 7 weeks after SCI, in comparison to the control groups. Scores demonstrated that the neurological function dramatically improved in treated rats. Thus, human umbilical cord blood-mesenchymal stem cell transplantation led to a significant improvement of behavior as well as the reduction of cavity volume after spinal cord injury.

Cells labelled with bromodeoxyuridine were counted in the ependymal and parenchymal regions. Proliferation of the newly generated cells increased greatly in treated rats as compared with the control rats. This demonstrated that the mesenchymal stem cells derived from the human umbilical cord blood could enhance proliferation of endogenous cells within the spinal cord. It was observed that both endogenous cell proliferation and oligogenesis contributed to functional recovery in the treatment group.
Rats were also examined for immunoreactivities. Results showed weak responses for the control groups, yet high responses for the treatment group. This suggests that the presence of mesenchymal stem cells creates an influential microenvironment within the spinal cord. Furthermore, transplantation of mesenchymal stem cells protected injured spinal cord cells from apoptosis.

Taken all his data together, treatment of spinal cord injuries with human umbilical cord blood-mesenchymal stem cells has a neuroregenerative and a neuroprotective effect which could be therapeutically used to treat spinal cord injuries.

===Lab 7===

''' ''Question 1a:'' ''' ''Provide a one sentence definition of a muscle satellite cell''

A muscle satellite cell is a quiescent stem cell present in muscle tissue between the sarcolema and the basal lamina of a muscle fiber, which becomes activated due to injury and allows for repair and regeneration of the muscle tissue.<ref><pubmed>12757751</pubmed></ref>

''' ''Question 1b:'' ''' ''In one paragraph, briefly discuss two examples of when satellite cells are activated''

Satellite cells are activated when muscle tissue needs to be repaired or regenerated. This is a result of injury or disease.

* Injury can be caused by various events. An example would be a bite from the Australian tiger snake, which contains the myotoxic agent notexin. <ref><pubmed>19415780</pubmed></ref> As studies have indicated, notexin causes the complete breakdown of muscle fibers and loss of functional capacity after 3 days. It was also shown that at 7 and 10 days after injection with notexin, muscles were comprised entirely of regenerating fibers.<ref><pubmed>16881061</pubmed></ref>

* Diseases can be another factor. The quickly worsening muscular disease Duchenne muscular dystrophy (DMD) is the result of a defective gene for dystrophin. Dystrophin is essential for connecting the muscle fiber cytoskeleton to the surrounding extracellular matrix.<ref><pubmed>5779432</pubmed></ref> Studies have shown that DMD results in elevated levels of satellite cells as compared to normal muscle tissue. <ref><pubmed>20467789</pubmed></ref> A mouse model of this disease was used for the first application of muscle stem cell transplantation. <ref><pubmed>2643055</pubmed></ref>

The following happens:

The quiescent satellite cells become activated and proliferate. Cells will then allign and fuse to allow for repair and/or regeneration of muscle fibers. [http://embryology.med.unsw.edu.au/embryology/images/0/02/Part_1_muscle_development_2012.pdf Injured muscle]

''' ''Question 2'' ''' ''In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury''

Spinal cord damage and other causes of long term injury affecting an innervating motor nerve will result in the partial or complete wasting away of the muscle - atrophy.<ref><pubmed>16940987</pubmed></ref> When considering both complete and incomplete injury to the spinal cord, one of the factors resulting in atrophy and a significant decrease in cross-sectional area of the muscle is the immobilisation and disuse of that tissue. <ref><pubmed>10483809</pubmed></ref> Studies have also shown that 6 weeks after the spinal cord injury took place, increased accumulation of intramuscular fat occurs in conjunction with the muscle atrophy. <ref><pubmed>15303112</pubmed></ref>

It was also noted that fast twitch type 2 muscle fibers became more numerous after complete or incomplete spinal cord injury, as compared to the slow twitch type 1 muscle fibers. <ref name="PMID9755066"><pubmed>9755066</pubmed></ref> It has been suggested that this change occurred as the muscle is no longer exercised on a long-term, consistent basis. It was also determined that in the particular study by Dupont-Versteegden ''et al.'' (1998), the affected muscle became more abundant in Myosin heavy chain type 2b. <ref name="PMID9755066"/> As a result, the muscle was more easily susceptible to fatigue.

===Lab 8===

'''Group 1'''

Firstly, the picture at the top immediately shows us the topic you are discussing: vision. This is good, but you might want to decrease the size slightly by stating the number of pixels in your file description. Your introduction includes the anatomy of the eye, which you should probably put under a separate heading. Expand the introduction a little and tell us what you will be presenting on your site.

The history is quite short – aim for more significant dates and discoveries and try to put them in an organised table. Within your history section you have images relating to development of the optic vesicle and lens. It seems like these should be incorporated in your next section on development. Good images though, but this time increase the size so the reader doesn’t have to open every single one of them to read the labels.

It seems like most work has gone into the section of development, which is good because we are focussing on the development of vision! The content relates really well and shows research has been done. There are a few sentences that strongly suggest they have been researched, however they are not references. This is in particular for the optic nerve and retina sections. Again, make sure the labels on the images can be read without having to open the file. You may also want to put the images together (optic nerve section) so the reader can easily see the changes happening during development. It is really good that you refer to the images within your text. The second half of your development section could do with a few images to complement the text. I personally think you should expand upon the lens development, because this is an important structure of the eye. What happens after migration into the embryo? If you find some related molecular information, eg. essential transcription factors, you could provide a brief explanation of these too and the role they play in vision development.

You started on your current research and a few references are present, as well as an image. I do not know what this image is and there is pretty much no text explaining any research that is currently undertaken. Please expand upon this!
The links should probably be listed under the heading ‘external links’ and as you expand upon certain sections, please keep adding to the glossary. For instance, I could not find the term ‘neuroblastic layer’ in the glossary (from the retina section).

With all of your images: please provide a title, description, source, copyright information, student image template. Some of your references will also need to be changed to avoid errors, citation of webpages and doubling-up of references. See the ‘editing basics’ on the embryology website.

'''Group 2'''

Your introduction is quite expansive and the first paragraph gives an excellent overview of what the somatosensory system actually is. At the end of the first paragraph you do refer to a picture; however, there is no picture. Please add this to show the somatosensory organisation within the body. In the second paragraph you mention some key timepoints related to the somatosensory development, which is good. After this (“Development of the system entails…lemniscal system.”) the text is probably too specific for the introduction. This can be used as an introduction for your development subheading. Please make sure that you edit the in-text references to proper references which we can access via your reference list. Also make sure you start adding terms to the glossary, eg. dorsal column-medial lemniscal system (I do not know what this means!)

You have started on your history section, but it would be more interesting and easier to read if you put this in a table. For instance: date – description – significant person. Also try to add a few more important discoveries. Again, please provide proper references. See the ‘editing basics’ section on this embryology website.

The central somatosensory differentiation is good and I can see that a lot of effort has been put into this section. The picture is very helpful and complements the text. To some extend it does seem like the sensory neurons only come from the dorsal aspect (going into the dorsal root ganglion), so maybe put a note in there that the dorsal and ventral rami are mixed nerves and both of them will contain sensory neurons that go to the dorsal root ganglion. With this image, you also have to include the student template. Text and references are good in this section and I particularly found the ‘making connections’ section very clear, organised and enjoyable to read. Do make sure that you add to the glossary – in particular terms from the ‘development of the primary cortex section’, and if possible add more images.

The touch section has a fair amount of text, but no images to complement it. This made it a bit boring to read. Make sure the subheadings stand out by making them bold. Most of the text has not been references at all, which is concerning and could potentially indicate plagiarism. I also did not read anything about the development of the various receptors (or hypotheses it no distinct evidence has been provided yet). Keep in mind we are looking at the development of the system, not the physiology. You did put in some interesting facts, such as that cell abnormalities can lead to Merkel-cell carcinoma.

Pain and hot/cold are similar to touch: good description of the physiology, but no development included. References are only provided as in-text citations or listed below, which will need to be edited to include them into the reference list. Include images to complement your text and engage the reader – this also concerns the touch section.

The pressure section has limited information regarding the development. Please include how this develops – what factors are included etc. In my opinion there is too much focus on the adult physiology. We are studying embryology… As mentioned above, please edit references and include appropriate images.

Current research looks good with an interesting image and the appropriate references, copyright and student template. The description helps to understand the image. Maybe add another research project to this section.

Add to the glossary, references and actually name the external links listed as 1) 2) and 3).

'''Group 3'''

Your introduction is quite good and gives us a brief overview of the different tastes. I also like it that you touch on the fact that it is important we recognise (via taste) food which would be dangerous to our health. In my opinion, after you mention the research (ending the sentence with …’may exist.’) you should tell the reader what you will be discussing on your page. The few lines on fatty acids does not seem to fit in, and should be part of your history section and possibly current/future research. Some specific information seems to have been researched, such as what umami codes for; however, references have not been provided. Also make sure that the image has the correct information – title, description, references, copyright, student template.

It would be more logical to put the history section next. Following this by the timeline and then go back to the cell biology, receptors and taste map etc.

The history section is good with many significant dates and clear descriptions incorporated in a table. I do see lots of numbers, which I think relate to references. I cannot find these references anywhere, so please edit this and make sure it is included in your list of references. There are also a few references listed in full in the table, so please put these down as proper references. Also, there is no good description for the year 2007 (it is mainly a reference).

The developmental timeline is expansive and very interesting! It really relates to the different developmental stages and tells us what happens over time. I hope you can include images with appropriate labels and information to this table, as it will greatly complement your text. Please do check your spelling, eg. ‘epithelium’ in week 6. Also references in this section are appropriate and are not doubled-up in the reference list. Do check reference 5 as it comes up with a cite error.

The section on cell biology and type 2 receptors is clear and easy to read. I cannot see any references though! Please be careful cause this might indicate plagiarism. The taste map is interesting and I am glad you mentioned research has indicated that the different receptors are in fact located all over the tongue – not just in particular sections. If possible, look for the original paper(s) that made this discovery.

The section on neural pathways is a little more difficult to read and I did not understand some of it. Particular terms are used in sentences which suggest little effort has been put in to explain everything in your own words. This is further indicated by the lack of references in the ‘first order neuron’ section and the majority of the ‘second order neuron’ section. I might be wrong, but then do add all your jargon to the glossary. If possible, also try to find other papers which present the same information to strengthen your points mentioned. Images for both the taste map and the cortex need referencing, copyright info, etc.

Adult tongue and taste buds. It is good you include some anatomy and physiology into your section. Do keep in mind the majority of your project should focus on embryonic development. You included the appropriate names, eg. sulcus terminalis, and I am glad to see that has also been put in the glossary. Some more terms do need to be added, eg. circumvallate. The text is good, clear and easy to read. Images are appropriate and relate to the text but need proper descriptions, citations, etc. A major let down of this section is the lack of references – please include this.

Personally, I found the abnormalities section very interesting! However, you are suddenly talking about all these genes and factors which you have not mentioned anywhere else. It might be good to provide a brief description of these in the development section or incorporate them into your developmental timeline. Images all have copyright information, but other information is missing, such as the student template and/or reference. Please check and add this.

Current research includes a lot of information. All different sections have their references which are displayed in the reference list. If you can, provide links to the website of the research groups working on current projects. Be careful not to just put your reference at the end, as you may also have to reference within the paragraph. Both pictures used will need the student template. The double tongue image will need a reference in its description too.

As mentioned before, add and edit the glossary and reference list. You should also add to the useful links (make this external links) and the image gallery, or delete these subheadings, as there is nothing there now.

'''Group 4'''

Your introduction is good and gives a brief overview of what the olfactory system entails. There were a few spelling mistakes, which can easily be corrected. Make sure you do tell the reader what you will be discussing on your page – development of the olfactory system and the particular subheadings you will focus on. The image could do with a few more labels for orientation, but besides that it complements the text and contains the correct citation, student template, etc.

The history section is good and quite extensively researched. Most groups will provide the history in a table, with dates in chronological order (to clearly show history and developing knowledge over time). This might be something to think about. I would suggest a ‘date – description – significant person’ type of format for a table. Good image, but it is displayed next to Pearson instead of Kollman. It is also difficult to see what it is and read the labels without opening the larger version, so you might want to increase its size slightly. Because this is a student image I would like to see the original – if possible provide a link to the Atlas of the Development of Man 2.
You should also explain what Kallmann’s Syndrome actually is, because this seems a little vague.

Your timeline of developmental process looks amazing and is enjoyable to read. Some of your words are printed in bold and link to the glossary. In one of your next sections the words link directly to the glossary, so you should probably do he same thing here. I really hope you can add pictures to this table to complement your text! Not quite sure what the line at the bottom (SINUSES:A:…) is doing there… either delete or expand upon this.

Structure: you only have a link here. Please provide text and image to explain the structure briefly. The YouTube link should be there to help the reader understand this section, instead of being the only thing this section is made up of. The video is not your own work, so please add your own work to this!

The normal function section was alright. It has some useful information in there, however, only a single reference listed at the end. It seemed like more references should be included within the paragraph. I would also include the fact that depolarization is an all-or-nothing response. The threshold needs to be reached for depolarization to occur, but there is no build-up over time to reach this threshold. It has to happen at that one instance. The links should be listed under the heading ‘external links’ or, if used as references, incorporated as proper references within the text. The olfactory bulb image is a little small and the description is quite brief. Though, good citation of the source and a student template is present.
I think the olfactory bulb image and the epithelium image should be included in the ‘structure’ section.

The abnormality section includes Kallmann’s syndrome and a quick definition has finally been provided! Please include this in the history section too. This section was a joy to read! Very interesting! A lot of effort has been put into the research and references have been done very well. I assume OB stands for olfactory bulb – please indicate this in the text. The dotpoints listed in the ‘clinical features’ section could do with a brief explanations instead of me having to scroll up and down between the text and the glossary. The image is excellent and shows a good simplified concept of what happens. Good descriptions, source citations, etc are added too. It was good to see diagnosis and treatment included.

Current research starts with a link, which seems quite random – include this in the external links section. You found some interesting and current research. References are only listed at the end of each paragraph, but should probably be included within as well. The image relates to one of the projects and descriptions are appropriate. Nothing has been added to the ‘role of odorant receptors’ though (apart from a reference). Please add a brief paragraph to this section.

Terms should be added to the glossary. The reference list also needs checking, because some are the same (eg. 11 & 12) and others do not have a reference (eg. 7 & 17).

'''Group 5'''

Your introduction is quite short, but it does state what you will be discussing on your page. You might want to include the normal development in the introduction, to allow for an overview of what normally happens before you actually start on the abnormal development. It just seems a little odd that you have abnormal vision as you title and then almost immediately after that you have a normal eye development heading.

I really like the chronological order used in the normal development section. It might be a bit easier to read if you use dot points. References seems to be fine, however, 4 and 5 are the same. It might also be useful to create a link to the group page on normal vision development.

Abnormal development consists of a few subheadings. Personally, I would delete the lines below the different subheadings. It will make it look more like one section on abnormal development. I think it was a good idea to look at the different parts of the eye related to abnormalities – lens, cornea, retina, etc. You look at different genes which play an important role at a certain developmental stage and you explain the resulting effects. I can see a lot of research has been done on this section. Images will need to be made bigger. They look insignificant with this size and it just seems like the text is going on and on. A lot of terms mentioned in this section are not included in the glossary, eg. Dysgenesis, substantia propria, CRX (what does it stand for?). Please add these in. Again, check your references, because some are the same, eg. 8 & 9.

Ocular manifestation is part of the abnormal development section (I think), so please make sure you show this with the headings. Again, immediately below this seems to be another heading with genetics, which has nothing included… or does LCA belong to genetics? I am a bit confused due to all your different headings and lines which seem to separate parts that may potentially belong together.

In your LCA section I would change the order of text a little: definition (as you have at the start), then epidemiology (which you have at the bottom), then the section on Dr Leber (up to “…placing great emphasis upon the high incidence of hereditary factors.”), lastly a new paragraph on the diagnosis (“As stated in the section on… diagnostic protocol for LCA”). The link to Abnormal Retinal Development does not work and will need editing. I can see that your timeline refers to LCA in particular and it is quite expansive. The one reference provided leads to a website with a timeline that seems to have been copied and pasted into your project. Please change this into your own words and (where possible) provide references to the original papers. The table also seems to be located in a strange position and it may be better to include this information in a table on history (in general), which you do not have at the moment. New research development also focuses on LCA only. Maybe create a separate section at the end where you can mention this and include more current research in brief paragraphs. The image relates well and has the appropriate citation, copyright and student template. The description could include a little more information.

Anophthalmia and microphthalmia are other genetic abnormalities described. Again, with the image you can expand slightly upon the description, but besides that it relates well to your text. Information provided is good, and includes the clinical description, genetic causes and management. Most important is that you use the same layout for your headings throughout your project. Within this one section you are using different subheadings and it all looks a bit chaotic and makes it less encouraging to read. You explain the role various genes play and I would like to know at what week/gestational stage they are important and can cause these abnormalities. Make sure all your references are correct, eg. There is no reference for 30.

It is probably good you only focused on 2 abnormalities caused by environmental factors. Images could really complement the text (although your whole page could probably use a few more images), so please add these. You include some relevant information and statistics, but make sure you also keep adding to the glossary. References are also the same for 45-48, hence these need editing.

In my opinion, firstly change the layout of your page and make it more organised with logical headings. Then focus on some of the other things mentioned above.

===Lab 9===

''' ''Question 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>22993381</pubmed>

Leptin levels are elevated in obese subjects and decreased in subjects restricted of food. This study investigates the effects of leptin concentrations on the development of the placenta and global placental gene expression profiles at d11.5.<ref name="PMID22993381"><pubmed>22993381</pubmed></ref> Pregnant mice were used and divided into 3 groups: control, mice that were undernourished and mice that were undernourished but supplemented with leptin. As stated in the study, "placentas from mothers exposed to food restriction preserved the placental labyrinth zone at the expense of the junctional zone, an effect abrogated in the restricted+ leptin group, which had a significant decrease in the labyrinth zone area compared to controls".<ref name="PMID22993381"/> Furthermore, when comparing the placentas from control and restricted+ leptin mothers there were 1128 genes which were differentially expressed. There were 281 differentially expressed genes between the control group and the restricted group.<ref name="PMID22993381"/>

This study concluded that being deprived of nutrition relates to a limited availability of energy and a decrease of the junctional zone of the placenta as mentioned above. When high levels of leptin are present, this response was altered and in fact the labyrinth zone had decreased.<ref name="PMID22993381"/>

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

Ectoderm, mesoderm and the neural crest contribute to the developing teeth.

Development of the teeth involves epithelial/mesenchymal interactions between the ectoderm of the first pharyngeal arch and cranial neural crest ectomesenchymal cells.

* The ectoderm from the first pharyngeal arch contributes to the enamel of the tooth. Some cells from the oral epithelium remain and differentiate locally into enamel-producing ameloblasts <ref name="PMID19266065"><pubmed>19266065</pubmed></ref>

* The majority of the dental papilla of the tooth has been demonstrated to be of neural crest origin. The cranial neural crest cells also give rise to various tooth cell types (odontoblasts, which produce dentine; cementoblast, which secrete cementum to cover the root dentine; osteoblasts, which participate in the formation of dental alveoli; and fibroblasts, which synthesize collagen for the periodontic ligament).<ref name="PMID19266065"/>

* During odontogenesis, non-neural crest cells have also been observed in the dental papilla region, which are mesodermally-derived migrating cells. These cells create a network of endothelial cells, contributing to the blood vessels in the pulp of the tooth.<ref><pubmed>21425080</pubmed></ref>

===Lab 11===
<pubmed>22984641</pubmed>

----
===References===
<references/>

2012 Group Project 6

2012-10-05T01:53:22Z

Z3333865: /* External Links */

[[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=#ADD8E6
|'''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=#87CEEB
| '''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=#ADD8E6
|''' 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=#87CEEB
| '''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=#ADD8E6
|'''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=#87CEEB
| '''1648''' ||Athanasius Kircher describes the ear trumpet: [http://www.ncbi.nlm.nih.gov/pubmed/10986798 Athanasius Kircher]
|- bgcolor=#ADD8E6
|'''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=#87CEEB
|'''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= #ADD8E6
|'''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= #87CEEB
|'''1789'''|| The membranous labyrinth is shown to consist of semicircular canals and the vestibular sacs. These form one system and are different to the periosteum. <ref><pubmed>11314703</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pubmed/11314703 Scarpa.]
|- bgcolor=#ADD8E6
| '''1831''' || It was discovered that the membranous labyrinth develops from a pit in the skin.It was also discovered that the spiral lamina is hollow. <ref><pubmed>1910378</pubmed></ref> [http://www.encyclopedia.com/doc/1G2-2830902099.html Huschke.]
|- bgcolor=#87CEEB
| '''1851''' || The cochlea is discovered in the inner ear, and parts of it, including the sensory epithelium, the spiral ganglion, the tectorial membrane, and the stria vascularis are described. [http://www.ncbi.nlm.nih.gov/pubmed/3517746 Alfonso Corti.]
|- bgcolor=#ADD8E6
|'''1898'''|| The first electric hearing aid, the Akouphone, was developed. A carbon transmitter allowed the hearing aid to be portable. [http://www.earhelp.co.uk/who-was-miller-reese-hutchinson.html Miller Reese Hutchison.]
|- bgcolor=#87CEEB
|'''1961'''|| Georg Von Békésy was awarded the Nobel Prize in Physiology or Medicine. He was awarded on this research on the sound waves at different frequencies on the nerve fibres. the research showed that the hair cells were activated along the cochlea correlated to the position of the cochlea. [http://www.ncbi.nlm.nih.gov/pubmed/14584991 Georg Von Békésy.]
|- bgcolor=#ADD8E6
|'''1978'''|| For the first time, a cochlear implant allowed a person to hear again. [http://www.abc.net.au/gnt/profiles/Transcripts/s1117832.htm Professor Graeme Clark.]
|- bgcolor=#87CEEB
| '''2012'''|| For the first time, human embryonic stem cells were used and proven to be effective in restoring hearing. See Current Research below and the [http://www.actiononhearingloss.org.uk/news-and-events/all-regions/press-releases/human-stem-cells-restore-hearing.aspx news article.]
|}

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

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

In order for mammals to hear, sound energy in the air has to move the hair cells located inside the inner ears of mammals. The ear provides us with the suitable apparatus to convert the longitudinal sound waves into mechanical ones in order to move the hair cells located in the inner ear.<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.<ref name="PMID11237469"/> 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 name="PMID11698185"><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. This forms as follows: <ref name="PMID11237469"/> <ref name="PMID17891709"/>
* 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.<ref name="PMID11237469"/> One of which is the EYA1 gene, which is imperative for formation of the pinna.<ref name="PMID9853969"><pubmed>9853969</pubmed></ref> Mice with a homologous Eya1 null gene either have malformed or absent ears. Since Eya1 gene plays a role in the formation of cartilage, its absence doesn’t allow the ear mesenchyme to convert into ear cartilage. <ref name="PMID14674478"><pubmed>14674478</pubmed></ref> Another gene important for pinna cartilage formation is the Bmp5 gene that is expressed later in development; mutations cause malformation of the perichondrium and thus cartilage formation.<ref><pubmed>7958439</pubmed></ref> Another gene important for early patterning of the pinna is the Hox2 gene.<ref name="PMID11698185"/> Mutations will lead to the 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 name="PMID14674478"/> <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. It forms as follows: <ref name="PMID11237469"/>
* 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, any mutation in the tympanic ring causes the abnormal growth of the EAM.<ref name="PMID10976045"><pubmed>10976045</pubmed></ref> 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.<ref name="PMID1441991"><pubmed>1441991</pubmed></ref> 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.<ref name="PMID1441991"/> Likewise for pinna formation Hox2 gene is also essential for differentiation of the pharyngeal arch into the tympanic ring and the formation of EAM.<ref name="PMID10976045"/> <ref name="PMID14674478"/>

===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.<ref name="PMID14674478"/> 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. <ref name="PMID10976045"/>

[[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 1st pharyngeal arch. <ref><pubmed>17346562</pubmed></ref>The 1st pharyngeal pouch (endodermal in origin) proliferates to giving rise to the tubotympanic recess at 3rd gestational week.<ref><pubmed>2921547</pubmed></ref> 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 name="PMID10976045"/>

'''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. <ref name="PMID18803631"><pubmed>18803631</pubmed></ref>

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. <ref name="PMID18803631"/> 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 name="PMID18803631"/>

[[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:1px 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==

*'''Caudal''': towards the embryonic tail

*'''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

*'''Inferior''': towards the bottom

*'''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

*'''Superior''': towards the top

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

*'''Tonotopic organisation''': the structural arrangement which allows for sounds of different frequencies to be detected and processed separately

*'''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]

[http://www.ncbi.nlm.nih.gov/pubmed/23033070 Study: Sound-induced length changes in outer hair cell stereocilia]

[http://www.ncbi.nlm.nih.gov/pubmed/22461562 Study: The role of hair cells, cilia and ciliary motility in otolith formation in the zebrafish otic vesicle]

[http://www.ncbi.nlm.nih.gov/pubmed/23026045 Study: Hearing restoration in a deaf animal model with intravenous transplantation of mesenchymal stem cells derived from human umbilical cord blood]

[http://www.youtube.com/watch?v=7O-adw-HyrQ Video: The process of hearing and how it works]

[http://www.youtube.com/watch?v=KGn9McPK7Qw Video: Deaf toddler finally hears his mom's voice]

{{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

2012-10-05T01:43:35Z

Z3333865: /* History */

[[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=#ADD8E6
|'''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=#87CEEB
| '''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=#ADD8E6
|''' 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=#87CEEB
| '''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=#ADD8E6
|'''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=#87CEEB
| '''1648''' ||Athanasius Kircher describes the ear trumpet: [http://www.ncbi.nlm.nih.gov/pubmed/10986798 Athanasius Kircher]
|- bgcolor=#ADD8E6
|'''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=#87CEEB
|'''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= #ADD8E6
|'''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= #87CEEB
|'''1789'''|| The membranous labyrinth is shown to consist of semicircular canals and the vestibular sacs. These form one system and are different to the periosteum. <ref><pubmed>11314703</pubmed></ref> [http://www.ncbi.nlm.nih.gov/pubmed/11314703 Scarpa.]
|- bgcolor=#ADD8E6
| '''1831''' || It was discovered that the membranous labyrinth develops from a pit in the skin.It was also discovered that the spiral lamina is hollow. <ref><pubmed>1910378</pubmed></ref> [http://www.encyclopedia.com/doc/1G2-2830902099.html Huschke.]
|- bgcolor=#87CEEB
| '''1851''' || The cochlea is discovered in the inner ear, and parts of it, including the sensory epithelium, the spiral ganglion, the tectorial membrane, and the stria vascularis are described. [http://www.ncbi.nlm.nih.gov/pubmed/3517746 Alfonso Corti.]
|- bgcolor=#ADD8E6
|'''1898'''|| The first electric hearing aid, the Akouphone, was developed. A carbon transmitter allowed the hearing aid to be portable. [http://www.earhelp.co.uk/who-was-miller-reese-hutchinson.html Miller Reese Hutchison.]
|- bgcolor=#87CEEB
|'''1961'''|| Georg Von Békésy was awarded the Nobel Prize in Physiology or Medicine. He was awarded on this research on the sound waves at different frequencies on the nerve fibres. the research showed that the hair cells were activated along the cochlea correlated to the position of the cochlea. [http://www.ncbi.nlm.nih.gov/pubmed/14584991 Georg Von Békésy.]
|- bgcolor=#ADD8E6
|'''1978'''|| For the first time, a cochlear implant allowed a person to hear again. [http://www.abc.net.au/gnt/profiles/Transcripts/s1117832.htm Professor Graeme Clark.]
|- bgcolor=#87CEEB
| '''2012'''|| For the first time, human embryonic stem cells were used and proven to be effective in restoring hearing. See Current Research below and the [http://www.actiononhearingloss.org.uk/news-and-events/all-regions/press-releases/human-stem-cells-restore-hearing.aspx news article.]
|}

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

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

In order for mammals to hear, sound energy in the air has to move the hair cells located inside the inner ears of mammals. The ear provides us with the suitable apparatus to convert the longitudinal sound waves into mechanical ones in order to move the hair cells located in the inner ear.<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.<ref name="PMID11237469"/> 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 name="PMID11698185"><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. This forms as follows: <ref name="PMID11237469"/> <ref name="PMID17891709"/>
* 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.<ref name="PMID11237469"/> One of which is the EYA1 gene, which is imperative for formation of the pinna.<ref name="PMID9853969"><pubmed>9853969</pubmed></ref> Mice with a homologous Eya1 null gene either have malformed or absent ears. Since Eya1 gene plays a role in the formation of cartilage, its absence doesn’t allow the ear mesenchyme to convert into ear cartilage. <ref name="PMID14674478"><pubmed>14674478</pubmed></ref> Another gene important for pinna cartilage formation is the Bmp5 gene that is expressed later in development; mutations cause malformation of the perichondrium and thus cartilage formation.<ref><pubmed>7958439</pubmed></ref> Another gene important for early patterning of the pinna is the Hox2 gene.<ref name="PMID11698185"/> Mutations will lead to the 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 name="PMID14674478"/> <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. It forms as follows: <ref name="PMID11237469"/>
* 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, any mutation in the tympanic ring causes the abnormal growth of the EAM.<ref name="PMID10976045"><pubmed>10976045</pubmed></ref> 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.<ref name="PMID1441991"><pubmed>1441991</pubmed></ref> 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.<ref name="PMID1441991"/> Likewise for pinna formation Hox2 gene is also essential for differentiation of the pharyngeal arch into the tympanic ring and the formation of EAM.<ref name="PMID10976045"/> <ref name="PMID14674478"/>

===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.<ref name="PMID14674478"/> 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. <ref name="PMID10976045"/>

[[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 1st pharyngeal arch. <ref><pubmed>17346562</pubmed></ref>The 1st pharyngeal pouch (endodermal in origin) proliferates to giving rise to the tubotympanic recess at 3rd gestational week.<ref><pubmed>2921547</pubmed></ref> 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 name="PMID10976045"/>

'''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. <ref name="PMID18803631"><pubmed>18803631</pubmed></ref>

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. <ref name="PMID18803631"/> 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 name="PMID18803631"/>

[[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:1px 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==

*'''Caudal''': towards the embryonic tail

*'''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

*'''Inferior''': towards the bottom

*'''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

*'''Superior''': towards the top

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

*'''Tonotopic organisation''': the structural arrangement which allows for sounds of different frequencies to be detected and processed separately

*'''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

2012-10-05T01:35:05Z

Z3333865: /* History */

[[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=#ADD8E6
|'''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=#87CEEB
| '''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=#ADD8E6
|''' 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=#87CEEB
| '''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=#ADD8E6
|'''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=#87CEEB
| '''1648''' ||Athanasius Kircher describes the ear trumpet: [http://www.ncbi.nlm.nih.gov/pubmed/10986798 Athanasius Kircher]
|- bgcolor=#ADD8E6
|'''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=#87CEEB
|'''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= #ADD8E6
|'''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= #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.<ref name="PMID11237469"/> 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 name="PMID11698185"><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. This forms as follows: <ref name="PMID11237469"/> <ref name="PMID17891709"/>
* 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.<ref name="PMID11237469"/> One of which is the EYA1 gene, which is imperative for formation of the pinna.<ref name="PMID9853969"><pubmed>9853969</pubmed></ref> Mice with a homologous Eya1 null gene either have malformed or absent ears. Since Eya1 gene plays a role in the formation of cartilage, its absence doesn’t allow the ear mesenchyme to convert into ear cartilage. <ref name="PMID14674478"><pubmed>14674478</pubmed></ref> Another gene important for pinna cartilage formation is the Bmp5 gene that is expressed later in development; mutations cause malformation of the perichondrium and thus cartilage formation.<ref><pubmed>7958439</pubmed></ref> Another gene important for early patterning of the pinna is the Hox2 gene.<ref name="PMID11698185"/> Mutations will lead to the 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 name="PMID14674478"/> <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. It forms as follows: <ref name="PMID11237469"/>
* 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, any mutation in the tympanic ring causes the abnormal growth of the EAM.<ref name="PMID10976045"><pubmed>10976045</pubmed></ref> 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.<ref name="PMID1441991"><pubmed>1441991</pubmed></ref> 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.<ref name="PMID1441991"/> Likewise for pinna formation Hox2 gene is also essential for differentiation of the pharyngeal arch into the tympanic ring and the formation of EAM.<ref name="PMID10976045"/> <ref name="PMID14674478"/>

===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.<ref name="PMID14674478"/> 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. <ref name="PMID10976045"/>

[[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 1st pharyngeal arch. <ref><pubmed>17346562</pubmed></ref>The 1st pharyngeal pouch (endodermal in origin) proliferates to giving rise to the tubotympanic recess at 3rd gestational week.<ref><pubmed>2921547</pubmed></ref> 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 name="PMID10976045"/>

'''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. <ref name="PMID18803631"><pubmed>18803631</pubmed></ref>

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. <ref name="PMID18803631"/> 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 name="PMID18803631"/>

[[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:1px 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==

*'''Caudal''': towards the embryonic tail

*'''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

*'''Inferior''': towards the bottom

*'''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

*'''Superior''': towards the top

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

*'''Tonotopic organisation''': the structural arrangement which allows for sounds of different frequencies to be detected and processed separately

*'''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.

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{{2012Projects}}

Talk:2012 Group Project 6

2012-10-05T01:10:43Z

Z3333865: /* 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==
Hey group 6!

It seems like we have pretty much finished our project. Please do not edit or add anything without letting the others know. I will be checking the discussion page frequently during the next hour or so, but if you don't get an immediate response just give me a call :) PLEASE DO NOT WORK ON THE PROJECT AFTER 12 NOON TODAY!!!

M.--[[User:Z3333865|Z3333865]] 11:10, 5 October 2012 (EST)
------

Hey everyone:)

So, one final morning to work on our project page! How exciting! Here a few things you have to check/complete for your section:

* Make sure all your '''references''' are correct - in-text references are needed as much as possible so we know where every sentence is coming from! I think it is just a few sections on the ouuter and middle ear that need changing, but please check!

* Check your '''spelling'''!

* Please add abbreviations, acronyms, and difficult words in general to the '''glossary'''. In alphabetical order that is and in your own words.

Also, I think we need 1 more image related to the external acoustic meatus (outer/middle ear section). If anyone comes across a good image with the appropriate copyright, please add this to the page.

Besides that.. Great work team! M. --[[User:Z3333865|Z3333865]] 22:08, 4 October 2012 (EST)
--------

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

2012-10-05T01:03:51Z

Z3333865: /* Summary inner 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.<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.<ref name="PMID11237469"/> 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 name="PMID11698185"><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. This forms as follows: <ref name="PMID11237469"/> <ref name="PMID17891709"/>
* 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.<ref name="PMID11237469"/> One of which is the EYA1 gene, which is imperative for formation of the pinna.<ref name="PMID9853969"><pubmed>9853969</pubmed></ref> Mice with a homologous Eya1 null gene either have malformed or absent ears. Since Eya1 gene plays a role in the formation of cartilage, its absence doesn’t allow the ear mesenchyme to convert into ear cartilage. <ref name="PMID14674478"><pubmed>14674478</pubmed></ref> Another gene important for pinna cartilage formation is the Bmp5 gene that is expressed later in development; mutations cause malformation of the perichondrium and thus cartilage formation.<ref><pubmed>7958439</pubmed></ref> Another gene important for early patterning of the pinna is the Hox2 gene.<ref name="PMID11698185"/> Mutations will lead to the 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 name="PMID14674478"/> <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. It forms as follows: <ref name="PMID11237469"/>
* 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, any mutation in the tympanic ring causes the abnormal growth of the EAM.<ref name="PMID10976045"><pubmed>10976045</pubmed></ref> 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.<ref name="PMID1441991"><pubmed>1441991</pubmed></ref> 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.<ref name="PMID1441991"/> Likewise for pinna formation Hox2 gene is also essential for differentiation of the pharyngeal arch into the tympanic ring and the formation of EAM.<ref name="PMID10976045"/> <ref name="PMID14674478"/>

===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.<ref name="PMID14674478"/> 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. <ref name="PMID10976045"/>

[[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 1st pharyngeal arch. <ref><pubmed>17346562</pubmed></ref>The 1st pharyngeal pouch (endodermal in origin) proliferates to giving rise to the tubotympanic recess at 3rd gestational week.<ref><pubmed>2921547</pubmed></ref> 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 name="PMID10976045"/>

'''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. <ref name="PMID18803631"><pubmed>18803631</pubmed></ref>

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. <ref name="PMID18803631"/> 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 name="PMID18803631"/>

[[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:1px 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==

*'''Caudal''': towards the embryonic tail

*'''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

*'''Inferior''': towards the bottom

*'''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

*'''Superior''': towards the top

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

*'''Tonotopic organisation''': the structural arrangement which allows for sounds of different frequencies to be detected and processed separately

*'''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

2012-10-05T00:58:55Z

Z3333865: /* Middle 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.<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.<ref name="PMID11237469"/> 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 name="PMID11698185"><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. This forms as follows: <ref name="PMID11237469"/> <ref name="PMID17891709"/>
* 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.<ref name="PMID11237469"/> One of which is the EYA1 gene, which is imperative for formation of the pinna.<ref name="PMID9853969"><pubmed>9853969</pubmed></ref> Mice with a homologous Eya1 null gene either have malformed or absent ears. Since Eya1 gene plays a role in the formation of cartilage, its absence doesn’t allow the ear mesenchyme to convert into ear cartilage. <ref name="PMID14674478"><pubmed>14674478</pubmed></ref> Another gene important for pinna cartilage formation is the Bmp5 gene that is expressed later in development; mutations cause malformation of the perichondrium and thus cartilage formation.<ref><pubmed>7958439</pubmed></ref> Another gene important for early patterning of the pinna is the Hox2 gene.<ref name="PMID11698185"/> Mutations will lead to the 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 name="PMID14674478"/> <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. It forms as follows: <ref name="PMID11237469"/>
* 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, any mutation in the tympanic ring causes the abnormal growth of the EAM.<ref name="PMID10976045"><pubmed>10976045</pubmed></ref> 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.<ref name="PMID1441991"><pubmed>1441991</pubmed></ref> 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.<ref name="PMID1441991"/> Likewise for pinna formation Hox2 gene is also essential for differentiation of the pharyngeal arch into the tympanic ring and the formation of EAM.<ref name="PMID10976045"/> <ref name="PMID14674478"/>

===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.<ref name="PMID14674478"/> 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. <ref name="PMID10976045"/>

[[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 1st pharyngeal arch. <ref><pubmed>17346562</pubmed></ref>The 1st pharyngeal pouch (endodermal in origin) proliferates to giving rise to the tubotympanic recess at 3rd gestational week.<ref><pubmed>2921547</pubmed></ref> 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 name="PMID10976045"/>

'''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. <ref name="PMID18803631"><pubmed>18803631</pubmed></ref>

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. <ref name="PMID18803631"/> 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 name="PMID18803631"/>

[[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==

*'''Caudal''': towards the embryonic tail

*'''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

*'''Inferior''': towards the bottom

*'''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

*'''Superior''': towards the top

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

*'''Tonotopic organisation''': the structural arrangement which allows for sounds of different frequencies to be detected and processed separately

*'''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

2012-10-05T00:57:38Z

Z3333865: /* Middle 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.<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.<ref name="PMID11237469"/> 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 name="PMID11698185"><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. This forms as follows: <ref name="PMID11237469"/> <ref name="PMID17891709"/>
* 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.<ref name="PMID11237469"/> One of which is the EYA1 gene, which is imperative for formation of the pinna.<ref name="PMID9853969"><pubmed>9853969</pubmed></ref> Mice with a homologous Eya1 null gene either have malformed or absent ears. Since Eya1 gene plays a role in the formation of cartilage, its absence doesn’t allow the ear mesenchyme to convert into ear cartilage. <ref name="PMID14674478"><pubmed>14674478</pubmed></ref> Another gene important for pinna cartilage formation is the Bmp5 gene that is expressed later in development; mutations cause malformation of the perichondrium and thus cartilage formation.<ref><pubmed>7958439</pubmed></ref> Another gene important for early patterning of the pinna is the Hox2 gene.<ref name="PMID11698185"/> Mutations will lead to the 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 name="PMID14674478"/> <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. It forms as follows: <ref name="PMID11237469"/>
* 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, any mutation in the tympanic ring causes the abnormal growth of the EAM.<ref name="PMID10976045"><pubmed>10976045</pubmed></ref> 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.<ref name="PMID1441991"><pubmed>1441991</pubmed></ref> 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.<ref name="PMID1441991"/> Likewise for pinna formation Hox2 gene is also essential for differentiation of the pharyngeal arch into the tympanic ring and the formation of EAM.<ref name="PMID10976045"/> <ref name="PMID14674478"/>

===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.<ref name="PMID14674478"/> 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. <ref name="PMID10976045"/>

[[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 1st pharyngeal arch. <ref><pubmed>17346562</pubmed></ref>The 1st pharyngeal pouch (endodermal in origin) proliferates to giving rise to the tubotympanic recess at 3rd gestational week.<ref><pubmed>2921547</pubmed></ref> 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 name="PMID10976045"/>

'''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. <ref name="PMID18803631"><pubmed>18803631</pubmed></ref>

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. <ref name="PMID18803631"/> 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 name="PMID18803631"/>

[[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==

*'''Caudal''': towards the embryonic tail

*'''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

*'''Inferior''': towards the bottom

*'''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

*'''Superior''': towards the top

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

*'''Tonotopic organisation''': the structural arrangement which allows for sounds of different frequencies to be detected and processed separately

*'''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

2012-10-05T00:30:56Z

Z3333865: /* 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.<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.<ref name="PMID11237469"/> 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 name="PMID11698185"><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. This forms as follows: <ref name="PMID11237469"/> <ref name="PMID17891709"/>
* 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.<ref name="PMID11237469"/> One of which is the EYA1 gene, which is imperative for formation of the pinna.<ref name="PMID9853969"><pubmed>9853969</pubmed></ref> Mice with a homologous Eya1 null gene either have malformed or absent ears. Since Eya1 gene plays a role in the formation of cartilage, its absence doesn’t allow the ear mesenchyme to convert into ear cartilage. <ref name="PMID14674478"><pubmed>14674478</pubmed></ref> Another gene important for pinna cartilage formation is the Bmp5 gene that is expressed later in development; mutations cause malformation of the perichondrium and thus cartilage formation.<ref><pubmed>7958439</pubmed></ref> Another gene important for early patterning of the pinna is the Hox2 gene.<ref name="PMID11698185"/> Mutations will lead to the 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 name="PMID14674478"/> <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. It forms as follows: <ref name="PMID11237469"/>
* 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, any mutation in the tympanic ring causes the abnormal growth of the EAM.<ref name="PMID10976045"><pubmed>10976045</pubmed></ref> 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.<ref name="PMID1441991"><pubmed>1441991</pubmed></ref> 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.<ref name="PMID1441991"/> Likewise for pinna formation Hox2 gene is also essential for differentiation of the pharyngeal arch into the tympanic ring and the formation of EAM.<ref name="PMID10976045"/> <ref name="PMID14674478"/>

===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==

*'''Caudal''': towards the embryonic tail

*'''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

*'''Inferior''': towards the bottom

*'''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

*'''Superior''': towards the top

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

*'''Tonotopic organisation''': the structural arrangement which allows for sounds of different frequencies to be detected and processed separately

*'''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

2012-10-05T00:22:05Z

Z3333865: /* Development */

[[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.<ref name="PMID11237469"/> 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 name="PMID11698185"><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. This forms as follows: <ref name="PMID11237469"/> <ref name="PMID17891709"/>
* 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.<ref name="PMID11237469"/> One of which is the EYA1 gene, which is imperative for formation of the pinna.<ref name="PMID9853969"><pubmed>9853969</pubmed></ref> Mice with a homologous Eya1 null gene either have malformed or absent ears. Since Eya1 gene plays a role in the formation of cartilage, its absence doesn’t allow the ear mesenchyme to convert into ear cartilage. <ref name="PMID14674478"><pubmed>14674478</pubmed></ref> Another gene important for pinna cartilage formation is the Bmp5 gene that is expressed later in development; mutations cause malformation of the perichondrium and thus cartilage formation.<ref><pubmed>7958439</pubmed></ref> Another gene important for early patterning of the pinna is the Hox2 gene.<ref name="PMID11698185"/> Mutations will lead to the 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 name="PMID14674478"/> <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==

*'''Caudal''': towards the embryonic tail

*'''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

*'''Inferior''': towards the bottom

*'''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

*'''Superior''': towards the top

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

*'''Tonotopic organisation''': the structural arrangement which allows for sounds of different frequencies to be detected and processed separately

*'''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

2012-10-04T23:57:34Z

Z3333865: /* Glossary */

[[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==

*'''Caudal''': towards the embryonic tail

*'''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

*'''Inferior''': towards the bottom

*'''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

*'''Superior''': towards the top

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

*'''Tonotopic organisation''': the structural arrangement which allows for sounds of different frequencies to be detected and processed separately

*'''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

2012-10-04T23:51:05Z

Z3333865: /* The Otocyst */

[[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 saccule.<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

2012-10-04T23:48:00Z

Z3333865: /* Glossary */

[[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==

===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

2012-10-04T23:41:22Z

Z3333865: /* 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.<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==

===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

*'''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

*'''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.

*'''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

2012-10-04T23:38:12Z

Z3333865: /* 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.<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. 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==

*'''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

*'''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

*'''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.

*'''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

2012-10-04T23:32:48Z

Z3333865: /* Glossary */

[[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==

*'''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

*'''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

*'''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.

*'''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

2012-10-04T23:31:30Z

Z3333865: /* Glossary */

[[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==

*'''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

*'''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

*'''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.

*'''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 [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

2012-10-04T23:26:07Z

Z3333865: /* Glossary */

[[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==

*'''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

*'''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

*'''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.

*'''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

== 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

2012-10-04T22:10:28Z

Z3333865: /* Inner 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. 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.

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{{2012Projects}}

Talk:2012 Group Project 6

2012-10-04T12:08:48Z

Z3333865: /* 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==
Hey everyone:)

So, one final morning to work on our project page! How exciting! Here a few things you have to check/complete for your section:

* Make sure all your '''references''' are correct - in-text references are needed as much as possible so we know where every sentence is coming from! I think it is just a few sections on the ouuter and middle ear that need changing, but please check!

* Check your '''spelling'''!

* Please add abbreviations, acronyms, and difficult words in general to the '''glossary'''. In alphabetical order that is and in your own words.

Also, I think we need 1 more image related to the external acoustic meatus (outer/middle ear section). If anyone comes across a good image with the appropriate copyright, please add this to the page.

Besides that.. Great work team! M. --[[User:Z3333865|Z3333865]] 22:08, 4 October 2012 (EST)
--------

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)
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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)

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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)
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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)
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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)

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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)

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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

2012-10-04T12:02:15Z

Z3333865: /* Image Gallery */

[[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. 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|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

2012-10-04T11:41:57Z

Z3333865:

[[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. 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|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: 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: cochlea stereocilia bundle.jpg|Stereocilia bundles in the normal cochlea
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: 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: 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.

</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

2012-10-04T11:38:51Z

Z3333865: /* 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. 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. 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|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: 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: cochlea stereocilia bundle.jpg|Stereocilia bundles in the normal cochlea
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: 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: 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.

</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

2012-10-04T11:33:47Z

Z3333865: /* Summary inner 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. 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.

[[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. 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|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: 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: cochlea stereocilia bundle.jpg|Stereocilia bundles in the normal cochlea
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: 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: 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.

</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

2012-10-04T11:32:20Z

Z3333865: /* Summary inner 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. 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.

[[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. 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|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 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: 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: cochlea stereocilia bundle.jpg|Stereocilia bundles in the normal cochlea
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: 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: 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.

</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

2012-10-04T11:27:32Z

Z3333865: /* Middle 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. 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.

[[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. 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|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'''
|- 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: 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: 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: cochlea stereocilia bundle.jpg|Stereocilia bundles in the normal cochlea
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: 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: 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.

</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

2012-10-04T11:26:07Z

Z3333865: /* Middle 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. 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.
[[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. 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|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'''
|- 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: 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: 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: cochlea stereocilia bundle.jpg|Stereocilia bundles in the normal cochlea
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: 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: 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.

</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}}