Embryology - User contributions [en-gb]

User:Z3374215

2012-10-16T23:08:17Z

Z3374215: /* Lab Attendance */

==Lab Attendance==

Lab 1 --[[User:Z3374215|Z3374215]] 11:49, 25 July 2012 (EST)

Lab 2 --[[User:Z3374215|Z3374215]] 10:06, 1 August 2012 (EST)

Lab 3 --[[User:Z3374215|Z3374215]] 10:06, 8 August 2012 (EST)

Lab 4 --[[User:Z3374215|Z3374215]] 12:01, 15 August 2012 (EST)

Lab 5 --[[User:Z3374215|Z3374215]] 10:05, 22 August 2012 (EST)

Lab 6 --[[User:Z3374215|Z3374215]] 10:08, 29 August 2012 (EST)

Lab 7 --[[User:Z3374215|Z3374215]] 10:14, 12 September 2012 (EST)

Lab 8 --[[User:Z3374215|Z3374215]] 11:34, 19 September 2012 (EST)

Lab 9 --[[User:Z3374215|Z3374215]] 10:10, 26 September 2012 (EST)

Lab 10 --[[User:Z3374215|Z3374215]] 10:04, 3 October 2012 (EST)

Lab 11 --[[User:Z3374215|Z3374215]] 11:57, 10 October 2012 (EST)

Lab 12 --[[User:Z3374215|Z3374215]] 10:08, 17 October 2012 (EST)

==Lab 1 Assessment==
'''1) Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.'''

The Nobel Prize for physiology or medicine in 2010 was awarded to Robert G. Edwards for his efforts in the development of In Vitro fertilization. Robert G. Edwards developed the idea of In Vitro fertilization since the 1950s. He first made fundamental discoveries in the life cycles of human eggs and the optimal time for fertilization before pairing with a gynecologist, Patrick Steptoe, and eventually seeing to the successful birth of an IVF baby in 1978. <ref>http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html</ref>.

'''2) Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).
'''
"The relative contributions of propulsive forces and receptor-ligand binding forces during early contact between spermatozoa and zona pellucida of oocyte" was published by the Journal of Theoretical Biology in Nov. 2011 <ref name= 'PMID22100500"><pubmed>22100500</pubmed></ref>. This report discusses the two main ways in which spermatozoa penetrate the zona pellucida of oocytes. The sperm utilize propulsive forces to assist in penetration. This is achieved through the motion of the flagella. The other factor important to penetration is the binding of sperm to ligands on the surface of the zona pellucida of the oocyte (ZP3). The report addresses the question of which of the cofactors is most imperative to the successful fertilization of the oocyte. A biomechanical model of the sperm-oocyte process was developed. It predicted that during early penetration the propulsive forces were stronger than the biochemical ligand binding. It was also predicted that the constant movement and overpowering force of the propulsion of sperm would make binding to ZP3 ligands difficult, making the large number of ZP3 receptors on the head of the sperm significantly important at this early stage.

===References===
<references/>

==Lab 2 Assessment==
'''1) Upload an image from a journal source relating to fertilization or the first 2 weeks of development as demonstrated in the practical class. Including in the image “Summary” window: An image name as a section heading, Any further description of what the image shows, A subsection labeled “Reference” and under this the original image source, appropriate reference and all copyright information and finally a template indicating that this is a student image.'''

'''Image:''' Expression of Endometrial CD98 in implantation<ref name:"PMID20976164"><pubmed>20976164</pubmed></ref>
[[Image:Expression of Endometrial CD98 in implantation.png|thumb|center|alt=Alt|Expression of Endometrial CD98 in implantation]]

'''2) Identify a protein associated with the implantation process, including a brief description of the protein's role (1-2 paragraphs).'''

A study has identified trophinin as a protein important to the adhesion implantation process. It is believed to be a single intrinsic protein that spans the membrane due to hydrophobic tendencies. This molecule can adhere without the aid of calcium unlike many cell adhesion molecules. Trophinin molecules bind with other trophinin molecule in trans structure on the cell surface. Immunostaining showed that antigens specific to the trophinin molecule can be found in both trophoblast cells and in the maternal epithelium near implantation sites of the embryo. The protein has been found to be encoded in the short arm of the X chromosome. It is also present in the mouse, sheep and bovine, along with monotremes and marsupials. It appears that the binding of the trophectoderm (consists of trophoblasts and is the connection between the blastocyst and the maternal cells) is essential to invasion and proliferation of cells. In embryonic cells trophinin induces and promotes invasion and proliferation. In maternal cells the same protein promotes apoptosis (controlled cell death) so as to allow the acceptance of the embryo. Therefore it is a dual signalling molecule. <ref name="PMID22717627"><pubmed>22717627</pubmed></ref>

===Reference===
<references/>

==Lab 3 Assessment==

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

The gestational age refers to the time since the last normal menstruation period<ref>Moore, K.L., 2011 ''The Developing Human'' 9th ed. W.B. Saunders</ref>. Whereas post-fertilisation age is calculated from the time of fertilization. There can be confusion between the terms espcially as gestational age is two weeks longer than post-fertilisation age<ref name:"PMID"15520122"><pubmed>15520122,</pubmed></ref>. Although in itself the term gestation age is confusing as there is no actual conceptus in until fertilisation but it is accepted by clinicians through widespread use<ref name:"PMID16006453"><pubmed>16006453</pubmed></ref>. As exact post-fetilisation age would be difficult to determine gestational age is used clinically. In assisted reproduction cases post-fertilisation age can be accurately determined but 2 weeks are generally added to age for ease of understanding<ref name:"PMID"15520122"><pubmed>15520122,</pubmed></ref>.

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

Somites form the dermis of the dorsal epithelium, skeletal muscles and some connective tissue, specifically, the vertebrae and ribs.<ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Paraxial Mesoderm: The Somites and Their Derivatives. Available from: http://www.ncbi.nlm.nih.gov/books/NBK10085/</ref>

===References===
<references/>

==Lab 4 Assessment==
'''1) Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.'''
Prenatal placental biopsy an invasive diagnostic technique for genetic abnormalities (such as trisomy 21) in the fetus. A karyotype is constructed allowing analysis of the chromosomes. It is used in the second and third trimester of pregnancy to confirm suspected malformations. Placental biopsies are sonographically guided<ref name:"PMID2712602"><pubmed>2712602</pubmed></ref>.
Chorionic villus testing is another invasive technique carried out transcervically in the first trimester to detect inherited disorders such as haemophilia <ref name:"PMID22250892"><pubmed>22250892</pubmed></ref>

'''2) Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''
Mesenchymal stem cells derived from the human umbilical cord have been used as a therapeutic treatment for neuromyelitis optica. Neuromyelitis optica is an autoimmune inflammatory disease that effects the optic nerve and spinal cord. Stem cells have been seen to provide differentiation potential to neural cells, secrete necessary factors and help regulate immunological function.
Five patients were treated with stem cell injections and then monitored for 18 months to analyse the effects both adverse and any improvements. Four out of the five patients gained some relief following treatment. Signs and symptoms decreased and the frequency of relapse was lessened. The neurological lesions also decreased in volume and severity as seen by MRI. The paper summarised that human umbilical cord stem cells were an appropriate therapy technique<ref name:"PMID22873728"><pubmed>22873728</pubmed></ref>.

===References===
<references/>

==Lab 7 Assessment==
'''1. (a) Provide a one sentence definition of a muscle satellite cell'''

Muscle satellite cells are progenitor cells and are involved in muscle growth and repair as they can induce regenerated muscle and additional satellite cells<ref name:”PMID12757751”><pubmed>12757751</pubmed></ref>

'''(b) In one paragraph, briefly discuss two examples of when satellite cells are activated.'''

A study investigating exercised induced satellite cell activation in skeletal muscle of growing and mature rats concluded that satellite cells are activated by acute sessions of prolonged eccentric exercise. It also concluded that exercise affected the proliferation of young mitotically active satellite cells<ref name:”PMID3693217”><pubmed>3693217</pubmed></ref>. Satellite cells are also activated when damage occurs. A study indicated that two variants of the IGF-I gene are necessary for activation of satellite cells. The study examined induced lesions to the anterior tibialis muscle of rats. The results showed that one variant of the gene which gives rise to a growth factor, MGF, is initially produced after injury and it activates satellite cells then IGF-IEa is expressed to maintain the repair process <ref>M Hill1, A Wernig, G Goldspink '''Muscle satellite (stem) cell activation during local tissue injury and repair''' Journal of Anatomy:2003, 203(1);89-99</ref>

'''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.'''

In a study involving 12 human patients suffering from spinal cord injuries a section of the vastus lateralis muscle was biopsied at 3 intervals within the first 6month following injury. From 6-24 weeks after injury they showed 27-56% atrophy of Type I, IIa and IIax+IIx fibers. There was increased conversion between muscle types, type IIa decreased and type IIax+IIx increased. However there was little change in proportion of tpye I fibers during this period<ref name:"PMID9887150"><pubmed>9887150</pubmed></ref>

===Reference===
<references/>

==Lab 8 Assessment - Peer Review==
===Vision===
The layout of the page is relatively good. If anything it appears little too image heavy at the moment. On the note of images, the referencing is good but don't forget to include the student template note with each image. The inclusion of some student drawn images in great to see but it might be an idea to make the labels larger as they are hard to read. The use of subheadings is great, a really logically well set out page. The references need a bit of work, some are spread sporadically throughout the page and some in the references section just list the URL along with the error on reference number 13.

The introductory is brief but alright. However the first two images are largely similar, not sure why both need to be included. Perhaps if possible it would be nice to link each of the main anatomical bullet points you have listed in your introduction to their associated developmental paragraph further down the page.

The History of development is coming along nicely but perhaps would be easier to read if it was in the format of a table. Also the Atlas of the Development of Man needs to be properly referenced with the author in the reference section. It would be nice to have some information relating to the pictures uploaded in this section.

The section on Development is well done and it is interesting to look at the individual development of each structure. It might be an idea to include some more references to when each structural development occurs. Current Research really needs some more content. The glossary is a nice addition and helpful.

===Somatosensory===
This page has made good use of subheadings ensuring that the main topics are easily accessible from the contents box. The project appears a little text heavy, it may help to include some other images. Also don't forget to add the student template note on the student drawn image. The reference list at the end is not particularly extensive. Perhaps this can be worked on by collecting the loose references in the text and adding them to the final reference section. Overall some sections of the page seem to have little to with embryology and more focused on adult function.

The introduction, while good, seems to lack any original voice, rather seeming to consist almost entirely of research done by others. The referencing in this section is also confusing with (Lagercrantz, Hanson, Evrard & Rodeck, 2001) being listed before any text. Referencing in this format also makes the page seem like a report or essay rather than a web page. There is also mention of a picture that does not exist. The historic section is brief and rather hard to digest as it is just a chunk of text. Perhaps putting this information into a table and developing it a little would help here.

The section on Central Somatosensory Differentiation was particularly well done. The inclusion of the student drawn image making all the difference. The general structure of this section is also commendable.

The subtitles "Touch", "Pain", "Heat/Cold" and "Pressure" are somewhat abrupt and don't particularly indicate what the section is discussing. This section in particular could do with the addition of some images. The information under Touch could perhaps be a little more heavily researched but is generally well written. Breaking the Pain section into some smaller paragraphs could be useful. The Hot/Cold and Pressure sections are well done excepting the random references to some articles.

Current research section could do with some more information. There are several words throughout the content that could do with being linked to an explanation in the glossary such as the "dorsal column-medial lemniscal system". The external links section is a good addition but it might be helpful to explain more clearly what each links to, especially the last three.

===Taste===
Initially the page seems to have a good balance between text and diagrams/photographs. However the figures included are not properly labelled once you click on the file and some of them don't appear to have any copyright information included. Some of the pictures could do with being a bit smaller as they take up a large proportion of the page. The student drawn image of the tongue is particularly impressive but does still need to have the student template included. The references seem limited in comparison to other groups perhaps suggesting a lack of depth or variety of research. There also appears to be a coding problem relating to reference number 5. The general layout and use of subheadings is great. It may be useful to link the words in the glossary to their occurrence in the text.

The introductory paragraphs are very well written. They are easy to understand and interesting and give a good overview of how taste functions. Similarly the section on taste map is well written clearly explaining the neurological factors associated with taste. However the presence of the picture in isolation is confusing as it is representing an the old method of taste association. Perhaps this would be resolved if a diagram of the newer taste map was also included. Also you say that the old taste map has been disproved by recent research but that research is not referenced. In fact it appears that very little of that section is referenced. The section on cortical areas is well done.

The timeline of developmental processes is good, the table an easy visual format and the information concise and effective. The only point of contention would be the direct quote in Wk8-9 which seems out of place in comparison to the remainder of the entries which are nicely paraphrased. The history section is similarly well done being extensive and comprehensive. That is excepting some Pub Med references which are just placed in the text rather than in the reference list at the bottom. While interesting and well written the part detailing the Adult Tongue and Taste Buds seems out of place in a embryology course.

The sections on the effect of gene expression on the formation of taste abnormalities and current research are good. However it may be useful to put the information regarding each picture as a caption rather than plain text.

It will be interesting to see what is put in the section "Image Gallery"

===Abnormal Vision===
Your introduction is relatively well written and the brief explanation of new terms such as microphthalmia was particularly useful. Perhaps it would be possible to break the text into two paragraphs to make reading easier.
It is really good to see a section included about normal eye development as it provides a basis of understanding for the remainder of the page. Concise and to the point and not too complex, it's great. Only suggestion would be to place it in a table perhaps with each Carnegie stage a new entry.

Layout of abnormalities is very logical covering the main areas of developmental abnormalities. However it is slightly confusing that immediately under the title Abnormal Lens Development more information on normal development is given. Allocating the defects to their associated individual genes is good but perhaps instead of a dotpoint a subheading would be of more use. The actual information is clearly and effectively written. The inclusion of the pictures clearly illustrates the abnormalities but their placement is a little odd. Perhaps they are too large. The captions on the pictures are appropriate and the pictures are appropriately referenced and it is great that the link to the picture contains more information.

Under the title "Ocular Manifestations" perhaps indicate what the two sections are, just so the following on sections make sense and don't appear disjointed. The sections on the genetic caused abnormalities is fascinating and very well written. The timeline included in the information about Leber Congenital Amaurosis is particularly interesting. The spacing in the section on genes associated with Anophthalmia and Microphthalmia appears slightly strange. The figures included are particularly illustrative and appropriate. Similarly the section on environmentally caused abnormalities is really well written and interesting.

Perhaps a more extensive section on current research could be included. If possible, link the words in the glossary to where they appeared in the text. This is the coding if you don't have it [[#Glossary|'''Words for Glossary''']]. Just add that in place of the word when you first mention it in the text. The citing and referencing is really well done. It also shows a great depth of research. The figures/photographs so far included are brilliant but the inclusion of a student drawn diagram somewhere if possible would be effective. Also try and fix the general layout of the project, possibly including some more subheadings. In general the content relates to the the course and is pitched at an appropriate level. Hope this helps.

===Hearing===
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.

==Lab 9==
'''1) Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

Hes1 is a target gene associated with notch signalling (a type of cell signaling pathway). It affects the proliferation and differentiation of progenitor cells. mic lacking the Hes 1 gene were observed to analyse the genes involvement in thyroid analyses. In a normal mouse the gene was expressed after E9.5. Hes1 lacking mice presented a smaller thyroid surface area at all stages and the fusion of the median anlage and ultimobranchial bodies was significantly delayed. It was suggested that the Hes1 gene is important for control of final number of thyrocyte and C-cell progenitors and ensuring adequate differentiation and endocrine function of these cells<ref name = "PMID21364918"><pubmed>21364918</pubmed></ref>.

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

Teeth form from the ectodermal layer of the oral cavity in association with the surrounding mesoderm. Specialised ectodermal cells termed ameloblasts secrete enamel. Mesenchymal mesoderm is responsible for other dental structures. Other specialised cells involved in tooth formation include odonoblasts and cementoblasts.<ref>John F. Neas, 2002 ''Human Anatomy Fourth Edition'', Chapter 4, Benjamin Cummings. Sourced from: http://cwx.prenhall.com/bookbind/pubbooks/martini10/chapter4/custom3/deluxe-content.html </ref>

===References===
<references/>

==Lab 11==
'''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.'''
Recently induced pluripotent stem cells have been used to analyse the hematopoietic abnormalities caused by trisomy 21, more commonly known as Down Syndrome. It is very difficult and rather unethical to test use real patients in testing, iPS cells provide a way to do this. It was shown that the blood progenitors were present in usual numbers and did proliferate at a normal rate but there was enhanced formation of erythrocytes, reduced formation of myeloid cells and normal levels of megakaryocytes. Hence this study showed that patients of trisomy 21 abnormalities in species specific hematopoiesis. On a more general level it demonstrated the use of iPS cells in the early stages of life and development. <ref name= "PMID23045704"><pubmed>23045704</pubmed></ref>

===References===
<references/>

User:Z3374215

2012-10-12T01:33:58Z

Z3374215: /* Lab 11 */

==Lab Attendance==

Lab 1 --[[User:Z3374215|Z3374215]] 11:49, 25 July 2012 (EST)

Lab 2 --[[User:Z3374215|Z3374215]] 10:06, 1 August 2012 (EST)

Lab 3 --[[User:Z3374215|Z3374215]] 10:06, 8 August 2012 (EST)

Lab 4 --[[User:Z3374215|Z3374215]] 12:01, 15 August 2012 (EST)

Lab 5 --[[User:Z3374215|Z3374215]] 10:05, 22 August 2012 (EST)

Lab 6 --[[User:Z3374215|Z3374215]] 10:08, 29 August 2012 (EST)

Lab 7 --[[User:Z3374215|Z3374215]] 10:14, 12 September 2012 (EST)

Lab 8 --[[User:Z3374215|Z3374215]] 11:34, 19 September 2012 (EST)

Lab 9 --[[User:Z3374215|Z3374215]] 10:10, 26 September 2012 (EST)

Lab 10 --[[User:Z3374215|Z3374215]] 10:04, 3 October 2012 (EST)

Lab 11 --[[User:Z3374215|Z3374215]] 11:57, 10 October 2012 (EST)

==Lab 1 Assessment==
'''1) Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.'''

The Nobel Prize for physiology or medicine in 2010 was awarded to Robert G. Edwards for his efforts in the development of In Vitro fertilization. Robert G. Edwards developed the idea of In Vitro fertilization since the 1950s. He first made fundamental discoveries in the life cycles of human eggs and the optimal time for fertilization before pairing with a gynecologist, Patrick Steptoe, and eventually seeing to the successful birth of an IVF baby in 1978. <ref>http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html</ref>.

'''2) Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).
'''
"The relative contributions of propulsive forces and receptor-ligand binding forces during early contact between spermatozoa and zona pellucida of oocyte" was published by the Journal of Theoretical Biology in Nov. 2011 <ref name= 'PMID22100500"><pubmed>22100500</pubmed></ref>. This report discusses the two main ways in which spermatozoa penetrate the zona pellucida of oocytes. The sperm utilize propulsive forces to assist in penetration. This is achieved through the motion of the flagella. The other factor important to penetration is the binding of sperm to ligands on the surface of the zona pellucida of the oocyte (ZP3). The report addresses the question of which of the cofactors is most imperative to the successful fertilization of the oocyte. A biomechanical model of the sperm-oocyte process was developed. It predicted that during early penetration the propulsive forces were stronger than the biochemical ligand binding. It was also predicted that the constant movement and overpowering force of the propulsion of sperm would make binding to ZP3 ligands difficult, making the large number of ZP3 receptors on the head of the sperm significantly important at this early stage.

===References===
<references/>

==Lab 2 Assessment==
'''1) Upload an image from a journal source relating to fertilization or the first 2 weeks of development as demonstrated in the practical class. Including in the image “Summary” window: An image name as a section heading, Any further description of what the image shows, A subsection labeled “Reference” and under this the original image source, appropriate reference and all copyright information and finally a template indicating that this is a student image.'''

'''Image:''' Expression of Endometrial CD98 in implantation<ref name:"PMID20976164"><pubmed>20976164</pubmed></ref>
[[Image:Expression of Endometrial CD98 in implantation.png|thumb|center|alt=Alt|Expression of Endometrial CD98 in implantation]]

'''2) Identify a protein associated with the implantation process, including a brief description of the protein's role (1-2 paragraphs).'''

A study has identified trophinin as a protein important to the adhesion implantation process. It is believed to be a single intrinsic protein that spans the membrane due to hydrophobic tendencies. This molecule can adhere without the aid of calcium unlike many cell adhesion molecules. Trophinin molecules bind with other trophinin molecule in trans structure on the cell surface. Immunostaining showed that antigens specific to the trophinin molecule can be found in both trophoblast cells and in the maternal epithelium near implantation sites of the embryo. The protein has been found to be encoded in the short arm of the X chromosome. It is also present in the mouse, sheep and bovine, along with monotremes and marsupials. It appears that the binding of the trophectoderm (consists of trophoblasts and is the connection between the blastocyst and the maternal cells) is essential to invasion and proliferation of cells. In embryonic cells trophinin induces and promotes invasion and proliferation. In maternal cells the same protein promotes apoptosis (controlled cell death) so as to allow the acceptance of the embryo. Therefore it is a dual signalling molecule. <ref name="PMID22717627"><pubmed>22717627</pubmed></ref>

===Reference===
<references/>

==Lab 3 Assessment==

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

The gestational age refers to the time since the last normal menstruation period<ref>Moore, K.L., 2011 ''The Developing Human'' 9th ed. W.B. Saunders</ref>. Whereas post-fertilisation age is calculated from the time of fertilization. There can be confusion between the terms espcially as gestational age is two weeks longer than post-fertilisation age<ref name:"PMID"15520122"><pubmed>15520122,</pubmed></ref>. Although in itself the term gestation age is confusing as there is no actual conceptus in until fertilisation but it is accepted by clinicians through widespread use<ref name:"PMID16006453"><pubmed>16006453</pubmed></ref>. As exact post-fetilisation age would be difficult to determine gestational age is used clinically. In assisted reproduction cases post-fertilisation age can be accurately determined but 2 weeks are generally added to age for ease of understanding<ref name:"PMID"15520122"><pubmed>15520122,</pubmed></ref>.

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

Somites form the dermis of the dorsal epithelium, skeletal muscles and some connective tissue, specifically, the vertebrae and ribs.<ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Paraxial Mesoderm: The Somites and Their Derivatives. Available from: http://www.ncbi.nlm.nih.gov/books/NBK10085/</ref>

===References===
<references/>

==Lab 4 Assessment==
'''1) Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.'''
Prenatal placental biopsy an invasive diagnostic technique for genetic abnormalities (such as trisomy 21) in the fetus. A karyotype is constructed allowing analysis of the chromosomes. It is used in the second and third trimester of pregnancy to confirm suspected malformations. Placental biopsies are sonographically guided<ref name:"PMID2712602"><pubmed>2712602</pubmed></ref>.
Chorionic villus testing is another invasive technique carried out transcervically in the first trimester to detect inherited disorders such as haemophilia <ref name:"PMID22250892"><pubmed>22250892</pubmed></ref>

'''2) Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''
Mesenchymal stem cells derived from the human umbilical cord have been used as a therapeutic treatment for neuromyelitis optica. Neuromyelitis optica is an autoimmune inflammatory disease that effects the optic nerve and spinal cord. Stem cells have been seen to provide differentiation potential to neural cells, secrete necessary factors and help regulate immunological function.
Five patients were treated with stem cell injections and then monitored for 18 months to analyse the effects both adverse and any improvements. Four out of the five patients gained some relief following treatment. Signs and symptoms decreased and the frequency of relapse was lessened. The neurological lesions also decreased in volume and severity as seen by MRI. The paper summarised that human umbilical cord stem cells were an appropriate therapy technique<ref name:"PMID22873728"><pubmed>22873728</pubmed></ref>.

===References===
<references/>

==Lab 7 Assessment==
'''1. (a) Provide a one sentence definition of a muscle satellite cell'''

Muscle satellite cells are progenitor cells and are involved in muscle growth and repair as they can induce regenerated muscle and additional satellite cells<ref name:”PMID12757751”><pubmed>12757751</pubmed></ref>

'''(b) In one paragraph, briefly discuss two examples of when satellite cells are activated.'''

A study investigating exercised induced satellite cell activation in skeletal muscle of growing and mature rats concluded that satellite cells are activated by acute sessions of prolonged eccentric exercise. It also concluded that exercise affected the proliferation of young mitotically active satellite cells<ref name:”PMID3693217”><pubmed>3693217</pubmed></ref>. Satellite cells are also activated when damage occurs. A study indicated that two variants of the IGF-I gene are necessary for activation of satellite cells. The study examined induced lesions to the anterior tibialis muscle of rats. The results showed that one variant of the gene which gives rise to a growth factor, MGF, is initially produced after injury and it activates satellite cells then IGF-IEa is expressed to maintain the repair process <ref>M Hill1, A Wernig, G Goldspink '''Muscle satellite (stem) cell activation during local tissue injury and repair''' Journal of Anatomy:2003, 203(1);89-99</ref>

'''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.'''

In a study involving 12 human patients suffering from spinal cord injuries a section of the vastus lateralis muscle was biopsied at 3 intervals within the first 6month following injury. From 6-24 weeks after injury they showed 27-56% atrophy of Type I, IIa and IIax+IIx fibers. There was increased conversion between muscle types, type IIa decreased and type IIax+IIx increased. However there was little change in proportion of tpye I fibers during this period<ref name:"PMID9887150"><pubmed>9887150</pubmed></ref>

===Reference===
<references/>

==Lab 8 Assessment - Peer Review==
===Vision===
The layout of the page is relatively good. If anything it appears little too image heavy at the moment. On the note of images, the referencing is good but don't forget to include the student template note with each image. The inclusion of some student drawn images in great to see but it might be an idea to make the labels larger as they are hard to read. The use of subheadings is great, a really logically well set out page. The references need a bit of work, some are spread sporadically throughout the page and some in the references section just list the URL along with the error on reference number 13.

The introductory is brief but alright. However the first two images are largely similar, not sure why both need to be included. Perhaps if possible it would be nice to link each of the main anatomical bullet points you have listed in your introduction to their associated developmental paragraph further down the page.

The History of development is coming along nicely but perhaps would be easier to read if it was in the format of a table. Also the Atlas of the Development of Man needs to be properly referenced with the author in the reference section. It would be nice to have some information relating to the pictures uploaded in this section.

The section on Development is well done and it is interesting to look at the individual development of each structure. It might be an idea to include some more references to when each structural development occurs. Current Research really needs some more content. The glossary is a nice addition and helpful.

===Somatosensory===
This page has made good use of subheadings ensuring that the main topics are easily accessible from the contents box. The project appears a little text heavy, it may help to include some other images. Also don't forget to add the student template note on the student drawn image. The reference list at the end is not particularly extensive. Perhaps this can be worked on by collecting the loose references in the text and adding them to the final reference section. Overall some sections of the page seem to have little to with embryology and more focused on adult function.

The introduction, while good, seems to lack any original voice, rather seeming to consist almost entirely of research done by others. The referencing in this section is also confusing with (Lagercrantz, Hanson, Evrard & Rodeck, 2001) being listed before any text. Referencing in this format also makes the page seem like a report or essay rather than a web page. There is also mention of a picture that does not exist. The historic section is brief and rather hard to digest as it is just a chunk of text. Perhaps putting this information into a table and developing it a little would help here.

The section on Central Somatosensory Differentiation was particularly well done. The inclusion of the student drawn image making all the difference. The general structure of this section is also commendable.

The subtitles "Touch", "Pain", "Heat/Cold" and "Pressure" are somewhat abrupt and don't particularly indicate what the section is discussing. This section in particular could do with the addition of some images. The information under Touch could perhaps be a little more heavily researched but is generally well written. Breaking the Pain section into some smaller paragraphs could be useful. The Hot/Cold and Pressure sections are well done excepting the random references to some articles.

Current research section could do with some more information. There are several words throughout the content that could do with being linked to an explanation in the glossary such as the "dorsal column-medial lemniscal system". The external links section is a good addition but it might be helpful to explain more clearly what each links to, especially the last three.

===Taste===
Initially the page seems to have a good balance between text and diagrams/photographs. However the figures included are not properly labelled once you click on the file and some of them don't appear to have any copyright information included. Some of the pictures could do with being a bit smaller as they take up a large proportion of the page. The student drawn image of the tongue is particularly impressive but does still need to have the student template included. The references seem limited in comparison to other groups perhaps suggesting a lack of depth or variety of research. There also appears to be a coding problem relating to reference number 5. The general layout and use of subheadings is great. It may be useful to link the words in the glossary to their occurrence in the text.

The introductory paragraphs are very well written. They are easy to understand and interesting and give a good overview of how taste functions. Similarly the section on taste map is well written clearly explaining the neurological factors associated with taste. However the presence of the picture in isolation is confusing as it is representing an the old method of taste association. Perhaps this would be resolved if a diagram of the newer taste map was also included. Also you say that the old taste map has been disproved by recent research but that research is not referenced. In fact it appears that very little of that section is referenced. The section on cortical areas is well done.

The timeline of developmental processes is good, the table an easy visual format and the information concise and effective. The only point of contention would be the direct quote in Wk8-9 which seems out of place in comparison to the remainder of the entries which are nicely paraphrased. The history section is similarly well done being extensive and comprehensive. That is excepting some Pub Med references which are just placed in the text rather than in the reference list at the bottom. While interesting and well written the part detailing the Adult Tongue and Taste Buds seems out of place in a embryology course.

The sections on the effect of gene expression on the formation of taste abnormalities and current research are good. However it may be useful to put the information regarding each picture as a caption rather than plain text.

It will be interesting to see what is put in the section "Image Gallery"

===Abnormal Vision===
Your introduction is relatively well written and the brief explanation of new terms such as microphthalmia was particularly useful. Perhaps it would be possible to break the text into two paragraphs to make reading easier.
It is really good to see a section included about normal eye development as it provides a basis of understanding for the remainder of the page. Concise and to the point and not too complex, it's great. Only suggestion would be to place it in a table perhaps with each Carnegie stage a new entry.

Layout of abnormalities is very logical covering the main areas of developmental abnormalities. However it is slightly confusing that immediately under the title Abnormal Lens Development more information on normal development is given. Allocating the defects to their associated individual genes is good but perhaps instead of a dotpoint a subheading would be of more use. The actual information is clearly and effectively written. The inclusion of the pictures clearly illustrates the abnormalities but their placement is a little odd. Perhaps they are too large. The captions on the pictures are appropriate and the pictures are appropriately referenced and it is great that the link to the picture contains more information.

Under the title "Ocular Manifestations" perhaps indicate what the two sections are, just so the following on sections make sense and don't appear disjointed. The sections on the genetic caused abnormalities is fascinating and very well written. The timeline included in the information about Leber Congenital Amaurosis is particularly interesting. The spacing in the section on genes associated with Anophthalmia and Microphthalmia appears slightly strange. The figures included are particularly illustrative and appropriate. Similarly the section on environmentally caused abnormalities is really well written and interesting.

Perhaps a more extensive section on current research could be included. If possible, link the words in the glossary to where they appeared in the text. This is the coding if you don't have it [[#Glossary|'''Words for Glossary''']]. Just add that in place of the word when you first mention it in the text. The citing and referencing is really well done. It also shows a great depth of research. The figures/photographs so far included are brilliant but the inclusion of a student drawn diagram somewhere if possible would be effective. Also try and fix the general layout of the project, possibly including some more subheadings. In general the content relates to the the course and is pitched at an appropriate level. Hope this helps.

===Hearing===
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.

==Lab 9==
'''1) Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

Hes1 is a target gene associated with notch signalling (a type of cell signaling pathway). It affects the proliferation and differentiation of progenitor cells. mic lacking the Hes 1 gene were observed to analyse the genes involvement in thyroid analyses. In a normal mouse the gene was expressed after E9.5. Hes1 lacking mice presented a smaller thyroid surface area at all stages and the fusion of the median anlage and ultimobranchial bodies was significantly delayed. It was suggested that the Hes1 gene is important for control of final number of thyrocyte and C-cell progenitors and ensuring adequate differentiation and endocrine function of these cells<ref name = "PMID21364918"><pubmed>21364918</pubmed></ref>.

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

Teeth form from the ectodermal layer of the oral cavity in association with the surrounding mesoderm. Specialised ectodermal cells termed ameloblasts secrete enamel. Mesenchymal mesoderm is responsible for other dental structures. Other specialised cells involved in tooth formation include odonoblasts and cementoblasts.<ref>John F. Neas, 2002 ''Human Anatomy Fourth Edition'', Chapter 4, Benjamin Cummings. Sourced from: http://cwx.prenhall.com/bookbind/pubbooks/martini10/chapter4/custom3/deluxe-content.html </ref>

===References===
<references/>

==Lab 11==
'''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.'''
Recently induced pluripotent stem cells have been used to analyse the hematopoietic abnormalities caused by trisomy 21, more commonly known as Down Syndrome. It is very difficult and rather unethical to test use real patients in testing, iPS cells provide a way to do this. It was shown that the blood progenitors were present in usual numbers and did proliferate at a normal rate but there was enhanced formation of erythrocytes, reduced formation of myeloid cells and normal levels of megakaryocytes. Hence this study showed that patients of trisomy 21 abnormalities in species specific hematopoiesis. On a more general level it demonstrated the use of iPS cells in the early stages of life and development. <ref name= "PMID23045704"><pubmed>23045704</pubmed></ref>

===References===
<references/>

User:Z3374215

2012-10-10T01:43:49Z

Z3374215: /* Lab 11 */

==Lab Attendance==

Lab 1 --[[User:Z3374215|Z3374215]] 11:49, 25 July 2012 (EST)

Lab 2 --[[User:Z3374215|Z3374215]] 10:06, 1 August 2012 (EST)

Lab 3 --[[User:Z3374215|Z3374215]] 10:06, 8 August 2012 (EST)

Lab 4 --[[User:Z3374215|Z3374215]] 12:01, 15 August 2012 (EST)

Lab 5 --[[User:Z3374215|Z3374215]] 10:05, 22 August 2012 (EST)

Lab 6 --[[User:Z3374215|Z3374215]] 10:08, 29 August 2012 (EST)

Lab 7 --[[User:Z3374215|Z3374215]] 10:14, 12 September 2012 (EST)

Lab 8 --[[User:Z3374215|Z3374215]] 11:34, 19 September 2012 (EST)

Lab 9 --[[User:Z3374215|Z3374215]] 10:10, 26 September 2012 (EST)

Lab 10 --[[User:Z3374215|Z3374215]] 10:04, 3 October 2012 (EST)

Lab 11 --[[User:Z3374215|Z3374215]] 11:57, 10 October 2012 (EST)

==Lab 1 Assessment==
'''1) Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.'''

The Nobel Prize for physiology or medicine in 2010 was awarded to Robert G. Edwards for his efforts in the development of In Vitro fertilization. Robert G. Edwards developed the idea of In Vitro fertilization since the 1950s. He first made fundamental discoveries in the life cycles of human eggs and the optimal time for fertilization before pairing with a gynecologist, Patrick Steptoe, and eventually seeing to the successful birth of an IVF baby in 1978. <ref>http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html</ref>.

'''2) Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).
'''
"The relative contributions of propulsive forces and receptor-ligand binding forces during early contact between spermatozoa and zona pellucida of oocyte" was published by the Journal of Theoretical Biology in Nov. 2011 <ref name= 'PMID22100500"><pubmed>22100500</pubmed></ref>. This report discusses the two main ways in which spermatozoa penetrate the zona pellucida of oocytes. The sperm utilize propulsive forces to assist in penetration. This is achieved through the motion of the flagella. The other factor important to penetration is the binding of sperm to ligands on the surface of the zona pellucida of the oocyte (ZP3). The report addresses the question of which of the cofactors is most imperative to the successful fertilization of the oocyte. A biomechanical model of the sperm-oocyte process was developed. It predicted that during early penetration the propulsive forces were stronger than the biochemical ligand binding. It was also predicted that the constant movement and overpowering force of the propulsion of sperm would make binding to ZP3 ligands difficult, making the large number of ZP3 receptors on the head of the sperm significantly important at this early stage.

===References===
<references/>

==Lab 2 Assessment==
'''1) Upload an image from a journal source relating to fertilization or the first 2 weeks of development as demonstrated in the practical class. Including in the image “Summary” window: An image name as a section heading, Any further description of what the image shows, A subsection labeled “Reference” and under this the original image source, appropriate reference and all copyright information and finally a template indicating that this is a student image.'''

'''Image:''' Expression of Endometrial CD98 in implantation<ref name:"PMID20976164"><pubmed>20976164</pubmed></ref>
[[Image:Expression of Endometrial CD98 in implantation.png|thumb|center|alt=Alt|Expression of Endometrial CD98 in implantation]]

'''2) Identify a protein associated with the implantation process, including a brief description of the protein's role (1-2 paragraphs).'''

A study has identified trophinin as a protein important to the adhesion implantation process. It is believed to be a single intrinsic protein that spans the membrane due to hydrophobic tendencies. This molecule can adhere without the aid of calcium unlike many cell adhesion molecules. Trophinin molecules bind with other trophinin molecule in trans structure on the cell surface. Immunostaining showed that antigens specific to the trophinin molecule can be found in both trophoblast cells and in the maternal epithelium near implantation sites of the embryo. The protein has been found to be encoded in the short arm of the X chromosome. It is also present in the mouse, sheep and bovine, along with monotremes and marsupials. It appears that the binding of the trophectoderm (consists of trophoblasts and is the connection between the blastocyst and the maternal cells) is essential to invasion and proliferation of cells. In embryonic cells trophinin induces and promotes invasion and proliferation. In maternal cells the same protein promotes apoptosis (controlled cell death) so as to allow the acceptance of the embryo. Therefore it is a dual signalling molecule. <ref name="PMID22717627"><pubmed>22717627</pubmed></ref>

===Reference===
<references/>

==Lab 3 Assessment==

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

The gestational age refers to the time since the last normal menstruation period<ref>Moore, K.L., 2011 ''The Developing Human'' 9th ed. W.B. Saunders</ref>. Whereas post-fertilisation age is calculated from the time of fertilization. There can be confusion between the terms espcially as gestational age is two weeks longer than post-fertilisation age<ref name:"PMID"15520122"><pubmed>15520122,</pubmed></ref>. Although in itself the term gestation age is confusing as there is no actual conceptus in until fertilisation but it is accepted by clinicians through widespread use<ref name:"PMID16006453"><pubmed>16006453</pubmed></ref>. As exact post-fetilisation age would be difficult to determine gestational age is used clinically. In assisted reproduction cases post-fertilisation age can be accurately determined but 2 weeks are generally added to age for ease of understanding<ref name:"PMID"15520122"><pubmed>15520122,</pubmed></ref>.

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

Somites form the dermis of the dorsal epithelium, skeletal muscles and some connective tissue, specifically, the vertebrae and ribs.<ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Paraxial Mesoderm: The Somites and Their Derivatives. Available from: http://www.ncbi.nlm.nih.gov/books/NBK10085/</ref>

===References===
<references/>

==Lab 4 Assessment==
'''1) Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.'''
Prenatal placental biopsy an invasive diagnostic technique for genetic abnormalities (such as trisomy 21) in the fetus. A karyotype is constructed allowing analysis of the chromosomes. It is used in the second and third trimester of pregnancy to confirm suspected malformations. Placental biopsies are sonographically guided<ref name:"PMID2712602"><pubmed>2712602</pubmed></ref>.
Chorionic villus testing is another invasive technique carried out transcervically in the first trimester to detect inherited disorders such as haemophilia <ref name:"PMID22250892"><pubmed>22250892</pubmed></ref>

'''2) Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''
Mesenchymal stem cells derived from the human umbilical cord have been used as a therapeutic treatment for neuromyelitis optica. Neuromyelitis optica is an autoimmune inflammatory disease that effects the optic nerve and spinal cord. Stem cells have been seen to provide differentiation potential to neural cells, secrete necessary factors and help regulate immunological function.
Five patients were treated with stem cell injections and then monitored for 18 months to analyse the effects both adverse and any improvements. Four out of the five patients gained some relief following treatment. Signs and symptoms decreased and the frequency of relapse was lessened. The neurological lesions also decreased in volume and severity as seen by MRI. The paper summarised that human umbilical cord stem cells were an appropriate therapy technique<ref name:"PMID22873728"><pubmed>22873728</pubmed></ref>.

===References===
<references/>

==Lab 7 Assessment==
'''1. (a) Provide a one sentence definition of a muscle satellite cell'''

Muscle satellite cells are progenitor cells and are involved in muscle growth and repair as they can induce regenerated muscle and additional satellite cells<ref name:”PMID12757751”><pubmed>12757751</pubmed></ref>

'''(b) In one paragraph, briefly discuss two examples of when satellite cells are activated.'''

A study investigating exercised induced satellite cell activation in skeletal muscle of growing and mature rats concluded that satellite cells are activated by acute sessions of prolonged eccentric exercise. It also concluded that exercise affected the proliferation of young mitotically active satellite cells<ref name:”PMID3693217”><pubmed>3693217</pubmed></ref>. Satellite cells are also activated when damage occurs. A study indicated that two variants of the IGF-I gene are necessary for activation of satellite cells. The study examined induced lesions to the anterior tibialis muscle of rats. The results showed that one variant of the gene which gives rise to a growth factor, MGF, is initially produced after injury and it activates satellite cells then IGF-IEa is expressed to maintain the repair process <ref>M Hill1, A Wernig, G Goldspink '''Muscle satellite (stem) cell activation during local tissue injury and repair''' Journal of Anatomy:2003, 203(1);89-99</ref>

'''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.'''

In a study involving 12 human patients suffering from spinal cord injuries a section of the vastus lateralis muscle was biopsied at 3 intervals within the first 6month following injury. From 6-24 weeks after injury they showed 27-56% atrophy of Type I, IIa and IIax+IIx fibers. There was increased conversion between muscle types, type IIa decreased and type IIax+IIx increased. However there was little change in proportion of tpye I fibers during this period<ref name:"PMID9887150"><pubmed>9887150</pubmed></ref>

===Reference===
<references/>

==Lab 8 Assessment - Peer Review==
===Vision===
The layout of the page is relatively good. If anything it appears little too image heavy at the moment. On the note of images, the referencing is good but don't forget to include the student template note with each image. The inclusion of some student drawn images in great to see but it might be an idea to make the labels larger as they are hard to read. The use of subheadings is great, a really logically well set out page. The references need a bit of work, some are spread sporadically throughout the page and some in the references section just list the URL along with the error on reference number 13.

The introductory is brief but alright. However the first two images are largely similar, not sure why both need to be included. Perhaps if possible it would be nice to link each of the main anatomical bullet points you have listed in your introduction to their associated developmental paragraph further down the page.

The History of development is coming along nicely but perhaps would be easier to read if it was in the format of a table. Also the Atlas of the Development of Man needs to be properly referenced with the author in the reference section. It would be nice to have some information relating to the pictures uploaded in this section.

The section on Development is well done and it is interesting to look at the individual development of each structure. It might be an idea to include some more references to when each structural development occurs. Current Research really needs some more content. The glossary is a nice addition and helpful.

===Somatosensory===
This page has made good use of subheadings ensuring that the main topics are easily accessible from the contents box. The project appears a little text heavy, it may help to include some other images. Also don't forget to add the student template note on the student drawn image. The reference list at the end is not particularly extensive. Perhaps this can be worked on by collecting the loose references in the text and adding them to the final reference section. Overall some sections of the page seem to have little to with embryology and more focused on adult function.

The introduction, while good, seems to lack any original voice, rather seeming to consist almost entirely of research done by others. The referencing in this section is also confusing with (Lagercrantz, Hanson, Evrard & Rodeck, 2001) being listed before any text. Referencing in this format also makes the page seem like a report or essay rather than a web page. There is also mention of a picture that does not exist. The historic section is brief and rather hard to digest as it is just a chunk of text. Perhaps putting this information into a table and developing it a little would help here.

The section on Central Somatosensory Differentiation was particularly well done. The inclusion of the student drawn image making all the difference. The general structure of this section is also commendable.

The subtitles "Touch", "Pain", "Heat/Cold" and "Pressure" are somewhat abrupt and don't particularly indicate what the section is discussing. This section in particular could do with the addition of some images. The information under Touch could perhaps be a little more heavily researched but is generally well written. Breaking the Pain section into some smaller paragraphs could be useful. The Hot/Cold and Pressure sections are well done excepting the random references to some articles.

Current research section could do with some more information. There are several words throughout the content that could do with being linked to an explanation in the glossary such as the "dorsal column-medial lemniscal system". The external links section is a good addition but it might be helpful to explain more clearly what each links to, especially the last three.

===Taste===
Initially the page seems to have a good balance between text and diagrams/photographs. However the figures included are not properly labelled once you click on the file and some of them don't appear to have any copyright information included. Some of the pictures could do with being a bit smaller as they take up a large proportion of the page. The student drawn image of the tongue is particularly impressive but does still need to have the student template included. The references seem limited in comparison to other groups perhaps suggesting a lack of depth or variety of research. There also appears to be a coding problem relating to reference number 5. The general layout and use of subheadings is great. It may be useful to link the words in the glossary to their occurrence in the text.

The introductory paragraphs are very well written. They are easy to understand and interesting and give a good overview of how taste functions. Similarly the section on taste map is well written clearly explaining the neurological factors associated with taste. However the presence of the picture in isolation is confusing as it is representing an the old method of taste association. Perhaps this would be resolved if a diagram of the newer taste map was also included. Also you say that the old taste map has been disproved by recent research but that research is not referenced. In fact it appears that very little of that section is referenced. The section on cortical areas is well done.

The timeline of developmental processes is good, the table an easy visual format and the information concise and effective. The only point of contention would be the direct quote in Wk8-9 which seems out of place in comparison to the remainder of the entries which are nicely paraphrased. The history section is similarly well done being extensive and comprehensive. That is excepting some Pub Med references which are just placed in the text rather than in the reference list at the bottom. While interesting and well written the part detailing the Adult Tongue and Taste Buds seems out of place in a embryology course.

The sections on the effect of gene expression on the formation of taste abnormalities and current research are good. However it may be useful to put the information regarding each picture as a caption rather than plain text.

It will be interesting to see what is put in the section "Image Gallery"

===Abnormal Vision===
Your introduction is relatively well written and the brief explanation of new terms such as microphthalmia was particularly useful. Perhaps it would be possible to break the text into two paragraphs to make reading easier.
It is really good to see a section included about normal eye development as it provides a basis of understanding for the remainder of the page. Concise and to the point and not too complex, it's great. Only suggestion would be to place it in a table perhaps with each Carnegie stage a new entry.

Layout of abnormalities is very logical covering the main areas of developmental abnormalities. However it is slightly confusing that immediately under the title Abnormal Lens Development more information on normal development is given. Allocating the defects to their associated individual genes is good but perhaps instead of a dotpoint a subheading would be of more use. The actual information is clearly and effectively written. The inclusion of the pictures clearly illustrates the abnormalities but their placement is a little odd. Perhaps they are too large. The captions on the pictures are appropriate and the pictures are appropriately referenced and it is great that the link to the picture contains more information.

Under the title "Ocular Manifestations" perhaps indicate what the two sections are, just so the following on sections make sense and don't appear disjointed. The sections on the genetic caused abnormalities is fascinating and very well written. The timeline included in the information about Leber Congenital Amaurosis is particularly interesting. The spacing in the section on genes associated with Anophthalmia and Microphthalmia appears slightly strange. The figures included are particularly illustrative and appropriate. Similarly the section on environmentally caused abnormalities is really well written and interesting.

Perhaps a more extensive section on current research could be included. If possible, link the words in the glossary to where they appeared in the text. This is the coding if you don't have it [[#Glossary|'''Words for Glossary''']]. Just add that in place of the word when you first mention it in the text. The citing and referencing is really well done. It also shows a great depth of research. The figures/photographs so far included are brilliant but the inclusion of a student drawn diagram somewhere if possible would be effective. Also try and fix the general layout of the project, possibly including some more subheadings. In general the content relates to the the course and is pitched at an appropriate level. Hope this helps.

===Hearing===
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.

==Lab 9==
'''1) Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

Hes1 is a target gene associated with notch signalling (a type of cell signaling pathway). It affects the proliferation and differentiation of progenitor cells. mic lacking the Hes 1 gene were observed to analyse the genes involvement in thyroid analyses. In a normal mouse the gene was expressed after E9.5. Hes1 lacking mice presented a smaller thyroid surface area at all stages and the fusion of the median anlage and ultimobranchial bodies was significantly delayed. It was suggested that the Hes1 gene is important for control of final number of thyrocyte and C-cell progenitors and ensuring adequate differentiation and endocrine function of these cells<ref name = "PMID21364918"><pubmed>21364918</pubmed></ref>.

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

Teeth form from the ectodermal layer of the oral cavity in association with the surrounding mesoderm. Specialised ectodermal cells termed ameloblasts secrete enamel. Mesenchymal mesoderm is responsible for other dental structures. Other specialised cells involved in tooth formation include odonoblasts and cementoblasts.<ref>John F. Neas, 2002 ''Human Anatomy Fourth Edition'', Chapter 4, Benjamin Cummings. Sourced from: http://cwx.prenhall.com/bookbind/pubbooks/martini10/chapter4/custom3/deluxe-content.html </ref>

===References===
<references/>

==Lab 11==
'''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.'''

===References===

User:Z3374215

2012-10-10T01:40:20Z

Z3374215: /* Lab 9 */

==Lab Attendance==

Lab 1 --[[User:Z3374215|Z3374215]] 11:49, 25 July 2012 (EST)

Lab 2 --[[User:Z3374215|Z3374215]] 10:06, 1 August 2012 (EST)

Lab 3 --[[User:Z3374215|Z3374215]] 10:06, 8 August 2012 (EST)

Lab 4 --[[User:Z3374215|Z3374215]] 12:01, 15 August 2012 (EST)

Lab 5 --[[User:Z3374215|Z3374215]] 10:05, 22 August 2012 (EST)

Lab 6 --[[User:Z3374215|Z3374215]] 10:08, 29 August 2012 (EST)

Lab 7 --[[User:Z3374215|Z3374215]] 10:14, 12 September 2012 (EST)

Lab 8 --[[User:Z3374215|Z3374215]] 11:34, 19 September 2012 (EST)

Lab 9 --[[User:Z3374215|Z3374215]] 10:10, 26 September 2012 (EST)

Lab 10 --[[User:Z3374215|Z3374215]] 10:04, 3 October 2012 (EST)

Lab 11 --[[User:Z3374215|Z3374215]] 11:57, 10 October 2012 (EST)

==Lab 1 Assessment==
'''1) Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.'''

The Nobel Prize for physiology or medicine in 2010 was awarded to Robert G. Edwards for his efforts in the development of In Vitro fertilization. Robert G. Edwards developed the idea of In Vitro fertilization since the 1950s. He first made fundamental discoveries in the life cycles of human eggs and the optimal time for fertilization before pairing with a gynecologist, Patrick Steptoe, and eventually seeing to the successful birth of an IVF baby in 1978. <ref>http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html</ref>.

'''2) Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).
'''
"The relative contributions of propulsive forces and receptor-ligand binding forces during early contact between spermatozoa and zona pellucida of oocyte" was published by the Journal of Theoretical Biology in Nov. 2011 <ref name= 'PMID22100500"><pubmed>22100500</pubmed></ref>. This report discusses the two main ways in which spermatozoa penetrate the zona pellucida of oocytes. The sperm utilize propulsive forces to assist in penetration. This is achieved through the motion of the flagella. The other factor important to penetration is the binding of sperm to ligands on the surface of the zona pellucida of the oocyte (ZP3). The report addresses the question of which of the cofactors is most imperative to the successful fertilization of the oocyte. A biomechanical model of the sperm-oocyte process was developed. It predicted that during early penetration the propulsive forces were stronger than the biochemical ligand binding. It was also predicted that the constant movement and overpowering force of the propulsion of sperm would make binding to ZP3 ligands difficult, making the large number of ZP3 receptors on the head of the sperm significantly important at this early stage.

===References===
<references/>

==Lab 2 Assessment==
'''1) Upload an image from a journal source relating to fertilization or the first 2 weeks of development as demonstrated in the practical class. Including in the image “Summary” window: An image name as a section heading, Any further description of what the image shows, A subsection labeled “Reference” and under this the original image source, appropriate reference and all copyright information and finally a template indicating that this is a student image.'''

'''Image:''' Expression of Endometrial CD98 in implantation<ref name:"PMID20976164"><pubmed>20976164</pubmed></ref>
[[Image:Expression of Endometrial CD98 in implantation.png|thumb|center|alt=Alt|Expression of Endometrial CD98 in implantation]]

'''2) Identify a protein associated with the implantation process, including a brief description of the protein's role (1-2 paragraphs).'''

A study has identified trophinin as a protein important to the adhesion implantation process. It is believed to be a single intrinsic protein that spans the membrane due to hydrophobic tendencies. This molecule can adhere without the aid of calcium unlike many cell adhesion molecules. Trophinin molecules bind with other trophinin molecule in trans structure on the cell surface. Immunostaining showed that antigens specific to the trophinin molecule can be found in both trophoblast cells and in the maternal epithelium near implantation sites of the embryo. The protein has been found to be encoded in the short arm of the X chromosome. It is also present in the mouse, sheep and bovine, along with monotremes and marsupials. It appears that the binding of the trophectoderm (consists of trophoblasts and is the connection between the blastocyst and the maternal cells) is essential to invasion and proliferation of cells. In embryonic cells trophinin induces and promotes invasion and proliferation. In maternal cells the same protein promotes apoptosis (controlled cell death) so as to allow the acceptance of the embryo. Therefore it is a dual signalling molecule. <ref name="PMID22717627"><pubmed>22717627</pubmed></ref>

===Reference===
<references/>

==Lab 3 Assessment==

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

The gestational age refers to the time since the last normal menstruation period<ref>Moore, K.L., 2011 ''The Developing Human'' 9th ed. W.B. Saunders</ref>. Whereas post-fertilisation age is calculated from the time of fertilization. There can be confusion between the terms espcially as gestational age is two weeks longer than post-fertilisation age<ref name:"PMID"15520122"><pubmed>15520122,</pubmed></ref>. Although in itself the term gestation age is confusing as there is no actual conceptus in until fertilisation but it is accepted by clinicians through widespread use<ref name:"PMID16006453"><pubmed>16006453</pubmed></ref>. As exact post-fetilisation age would be difficult to determine gestational age is used clinically. In assisted reproduction cases post-fertilisation age can be accurately determined but 2 weeks are generally added to age for ease of understanding<ref name:"PMID"15520122"><pubmed>15520122,</pubmed></ref>.

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

Somites form the dermis of the dorsal epithelium, skeletal muscles and some connective tissue, specifically, the vertebrae and ribs.<ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Paraxial Mesoderm: The Somites and Their Derivatives. Available from: http://www.ncbi.nlm.nih.gov/books/NBK10085/</ref>

===References===
<references/>

==Lab 4 Assessment==
'''1) Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.'''
Prenatal placental biopsy an invasive diagnostic technique for genetic abnormalities (such as trisomy 21) in the fetus. A karyotype is constructed allowing analysis of the chromosomes. It is used in the second and third trimester of pregnancy to confirm suspected malformations. Placental biopsies are sonographically guided<ref name:"PMID2712602"><pubmed>2712602</pubmed></ref>.
Chorionic villus testing is another invasive technique carried out transcervically in the first trimester to detect inherited disorders such as haemophilia <ref name:"PMID22250892"><pubmed>22250892</pubmed></ref>

'''2) Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''
Mesenchymal stem cells derived from the human umbilical cord have been used as a therapeutic treatment for neuromyelitis optica. Neuromyelitis optica is an autoimmune inflammatory disease that effects the optic nerve and spinal cord. Stem cells have been seen to provide differentiation potential to neural cells, secrete necessary factors and help regulate immunological function.
Five patients were treated with stem cell injections and then monitored for 18 months to analyse the effects both adverse and any improvements. Four out of the five patients gained some relief following treatment. Signs and symptoms decreased and the frequency of relapse was lessened. The neurological lesions also decreased in volume and severity as seen by MRI. The paper summarised that human umbilical cord stem cells were an appropriate therapy technique<ref name:"PMID22873728"><pubmed>22873728</pubmed></ref>.

===References===
<references/>

==Lab 7 Assessment==
'''1. (a) Provide a one sentence definition of a muscle satellite cell'''

Muscle satellite cells are progenitor cells and are involved in muscle growth and repair as they can induce regenerated muscle and additional satellite cells<ref name:”PMID12757751”><pubmed>12757751</pubmed></ref>

'''(b) In one paragraph, briefly discuss two examples of when satellite cells are activated.'''

A study investigating exercised induced satellite cell activation in skeletal muscle of growing and mature rats concluded that satellite cells are activated by acute sessions of prolonged eccentric exercise. It also concluded that exercise affected the proliferation of young mitotically active satellite cells<ref name:”PMID3693217”><pubmed>3693217</pubmed></ref>. Satellite cells are also activated when damage occurs. A study indicated that two variants of the IGF-I gene are necessary for activation of satellite cells. The study examined induced lesions to the anterior tibialis muscle of rats. The results showed that one variant of the gene which gives rise to a growth factor, MGF, is initially produced after injury and it activates satellite cells then IGF-IEa is expressed to maintain the repair process <ref>M Hill1, A Wernig, G Goldspink '''Muscle satellite (stem) cell activation during local tissue injury and repair''' Journal of Anatomy:2003, 203(1);89-99</ref>

'''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.'''

In a study involving 12 human patients suffering from spinal cord injuries a section of the vastus lateralis muscle was biopsied at 3 intervals within the first 6month following injury. From 6-24 weeks after injury they showed 27-56% atrophy of Type I, IIa and IIax+IIx fibers. There was increased conversion between muscle types, type IIa decreased and type IIax+IIx increased. However there was little change in proportion of tpye I fibers during this period<ref name:"PMID9887150"><pubmed>9887150</pubmed></ref>

===Reference===
<references/>

==Lab 8 Assessment - Peer Review==
===Vision===
The layout of the page is relatively good. If anything it appears little too image heavy at the moment. On the note of images, the referencing is good but don't forget to include the student template note with each image. The inclusion of some student drawn images in great to see but it might be an idea to make the labels larger as they are hard to read. The use of subheadings is great, a really logically well set out page. The references need a bit of work, some are spread sporadically throughout the page and some in the references section just list the URL along with the error on reference number 13.

The introductory is brief but alright. However the first two images are largely similar, not sure why both need to be included. Perhaps if possible it would be nice to link each of the main anatomical bullet points you have listed in your introduction to their associated developmental paragraph further down the page.

The History of development is coming along nicely but perhaps would be easier to read if it was in the format of a table. Also the Atlas of the Development of Man needs to be properly referenced with the author in the reference section. It would be nice to have some information relating to the pictures uploaded in this section.

The section on Development is well done and it is interesting to look at the individual development of each structure. It might be an idea to include some more references to when each structural development occurs. Current Research really needs some more content. The glossary is a nice addition and helpful.

===Somatosensory===
This page has made good use of subheadings ensuring that the main topics are easily accessible from the contents box. The project appears a little text heavy, it may help to include some other images. Also don't forget to add the student template note on the student drawn image. The reference list at the end is not particularly extensive. Perhaps this can be worked on by collecting the loose references in the text and adding them to the final reference section. Overall some sections of the page seem to have little to with embryology and more focused on adult function.

The introduction, while good, seems to lack any original voice, rather seeming to consist almost entirely of research done by others. The referencing in this section is also confusing with (Lagercrantz, Hanson, Evrard & Rodeck, 2001) being listed before any text. Referencing in this format also makes the page seem like a report or essay rather than a web page. There is also mention of a picture that does not exist. The historic section is brief and rather hard to digest as it is just a chunk of text. Perhaps putting this information into a table and developing it a little would help here.

The section on Central Somatosensory Differentiation was particularly well done. The inclusion of the student drawn image making all the difference. The general structure of this section is also commendable.

The subtitles "Touch", "Pain", "Heat/Cold" and "Pressure" are somewhat abrupt and don't particularly indicate what the section is discussing. This section in particular could do with the addition of some images. The information under Touch could perhaps be a little more heavily researched but is generally well written. Breaking the Pain section into some smaller paragraphs could be useful. The Hot/Cold and Pressure sections are well done excepting the random references to some articles.

Current research section could do with some more information. There are several words throughout the content that could do with being linked to an explanation in the glossary such as the "dorsal column-medial lemniscal system". The external links section is a good addition but it might be helpful to explain more clearly what each links to, especially the last three.

===Taste===
Initially the page seems to have a good balance between text and diagrams/photographs. However the figures included are not properly labelled once you click on the file and some of them don't appear to have any copyright information included. Some of the pictures could do with being a bit smaller as they take up a large proportion of the page. The student drawn image of the tongue is particularly impressive but does still need to have the student template included. The references seem limited in comparison to other groups perhaps suggesting a lack of depth or variety of research. There also appears to be a coding problem relating to reference number 5. The general layout and use of subheadings is great. It may be useful to link the words in the glossary to their occurrence in the text.

The introductory paragraphs are very well written. They are easy to understand and interesting and give a good overview of how taste functions. Similarly the section on taste map is well written clearly explaining the neurological factors associated with taste. However the presence of the picture in isolation is confusing as it is representing an the old method of taste association. Perhaps this would be resolved if a diagram of the newer taste map was also included. Also you say that the old taste map has been disproved by recent research but that research is not referenced. In fact it appears that very little of that section is referenced. The section on cortical areas is well done.

The timeline of developmental processes is good, the table an easy visual format and the information concise and effective. The only point of contention would be the direct quote in Wk8-9 which seems out of place in comparison to the remainder of the entries which are nicely paraphrased. The history section is similarly well done being extensive and comprehensive. That is excepting some Pub Med references which are just placed in the text rather than in the reference list at the bottom. While interesting and well written the part detailing the Adult Tongue and Taste Buds seems out of place in a embryology course.

The sections on the effect of gene expression on the formation of taste abnormalities and current research are good. However it may be useful to put the information regarding each picture as a caption rather than plain text.

It will be interesting to see what is put in the section "Image Gallery"

===Abnormal Vision===
Your introduction is relatively well written and the brief explanation of new terms such as microphthalmia was particularly useful. Perhaps it would be possible to break the text into two paragraphs to make reading easier.
It is really good to see a section included about normal eye development as it provides a basis of understanding for the remainder of the page. Concise and to the point and not too complex, it's great. Only suggestion would be to place it in a table perhaps with each Carnegie stage a new entry.

Layout of abnormalities is very logical covering the main areas of developmental abnormalities. However it is slightly confusing that immediately under the title Abnormal Lens Development more information on normal development is given. Allocating the defects to their associated individual genes is good but perhaps instead of a dotpoint a subheading would be of more use. The actual information is clearly and effectively written. The inclusion of the pictures clearly illustrates the abnormalities but their placement is a little odd. Perhaps they are too large. The captions on the pictures are appropriate and the pictures are appropriately referenced and it is great that the link to the picture contains more information.

Under the title "Ocular Manifestations" perhaps indicate what the two sections are, just so the following on sections make sense and don't appear disjointed. The sections on the genetic caused abnormalities is fascinating and very well written. The timeline included in the information about Leber Congenital Amaurosis is particularly interesting. The spacing in the section on genes associated with Anophthalmia and Microphthalmia appears slightly strange. The figures included are particularly illustrative and appropriate. Similarly the section on environmentally caused abnormalities is really well written and interesting.

Perhaps a more extensive section on current research could be included. If possible, link the words in the glossary to where they appeared in the text. This is the coding if you don't have it [[#Glossary|'''Words for Glossary''']]. Just add that in place of the word when you first mention it in the text. The citing and referencing is really well done. It also shows a great depth of research. The figures/photographs so far included are brilliant but the inclusion of a student drawn diagram somewhere if possible would be effective. Also try and fix the general layout of the project, possibly including some more subheadings. In general the content relates to the the course and is pitched at an appropriate level. Hope this helps.

===Hearing===
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.

==Lab 9==
'''1) Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

Hes1 is a target gene associated with notch signalling (a type of cell signaling pathway). It affects the proliferation and differentiation of progenitor cells. mic lacking the Hes 1 gene were observed to analyse the genes involvement in thyroid analyses. In a normal mouse the gene was expressed after E9.5. Hes1 lacking mice presented a smaller thyroid surface area at all stages and the fusion of the median anlage and ultimobranchial bodies was significantly delayed. It was suggested that the Hes1 gene is important for control of final number of thyrocyte and C-cell progenitors and ensuring adequate differentiation and endocrine function of these cells<ref name = "PMID21364918"><pubmed>21364918</pubmed></ref>.

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

Teeth form from the ectodermal layer of the oral cavity in association with the surrounding mesoderm. Specialised ectodermal cells termed ameloblasts secrete enamel. Mesenchymal mesoderm is responsible for other dental structures. Other specialised cells involved in tooth formation include odonoblasts and cementoblasts.<ref>John F. Neas, 2002 ''Human Anatomy Fourth Edition'', Chapter 4, Benjamin Cummings. Sourced from: http://cwx.prenhall.com/bookbind/pubbooks/martini10/chapter4/custom3/deluxe-content.html </ref>

===References===
<references/>

==Lab 11==
===References===

User:Z3374215

2012-10-10T00:57:29Z

Z3374215: /* Lab Attendance */

==Lab Attendance==

Lab 1 --[[User:Z3374215|Z3374215]] 11:49, 25 July 2012 (EST)

Lab 2 --[[User:Z3374215|Z3374215]] 10:06, 1 August 2012 (EST)

Lab 3 --[[User:Z3374215|Z3374215]] 10:06, 8 August 2012 (EST)

Lab 4 --[[User:Z3374215|Z3374215]] 12:01, 15 August 2012 (EST)

Lab 5 --[[User:Z3374215|Z3374215]] 10:05, 22 August 2012 (EST)

Lab 6 --[[User:Z3374215|Z3374215]] 10:08, 29 August 2012 (EST)

Lab 7 --[[User:Z3374215|Z3374215]] 10:14, 12 September 2012 (EST)

Lab 8 --[[User:Z3374215|Z3374215]] 11:34, 19 September 2012 (EST)

Lab 9 --[[User:Z3374215|Z3374215]] 10:10, 26 September 2012 (EST)

Lab 10 --[[User:Z3374215|Z3374215]] 10:04, 3 October 2012 (EST)

Lab 11 --[[User:Z3374215|Z3374215]] 11:57, 10 October 2012 (EST)

==Lab 1 Assessment==
'''1) Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.'''

The Nobel Prize for physiology or medicine in 2010 was awarded to Robert G. Edwards for his efforts in the development of In Vitro fertilization. Robert G. Edwards developed the idea of In Vitro fertilization since the 1950s. He first made fundamental discoveries in the life cycles of human eggs and the optimal time for fertilization before pairing with a gynecologist, Patrick Steptoe, and eventually seeing to the successful birth of an IVF baby in 1978. <ref>http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html</ref>.

'''2) Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).
'''
"The relative contributions of propulsive forces and receptor-ligand binding forces during early contact between spermatozoa and zona pellucida of oocyte" was published by the Journal of Theoretical Biology in Nov. 2011 <ref name= 'PMID22100500"><pubmed>22100500</pubmed></ref>. This report discusses the two main ways in which spermatozoa penetrate the zona pellucida of oocytes. The sperm utilize propulsive forces to assist in penetration. This is achieved through the motion of the flagella. The other factor important to penetration is the binding of sperm to ligands on the surface of the zona pellucida of the oocyte (ZP3). The report addresses the question of which of the cofactors is most imperative to the successful fertilization of the oocyte. A biomechanical model of the sperm-oocyte process was developed. It predicted that during early penetration the propulsive forces were stronger than the biochemical ligand binding. It was also predicted that the constant movement and overpowering force of the propulsion of sperm would make binding to ZP3 ligands difficult, making the large number of ZP3 receptors on the head of the sperm significantly important at this early stage.

===References===
<references/>

==Lab 2 Assessment==
'''1) Upload an image from a journal source relating to fertilization or the first 2 weeks of development as demonstrated in the practical class. Including in the image “Summary” window: An image name as a section heading, Any further description of what the image shows, A subsection labeled “Reference” and under this the original image source, appropriate reference and all copyright information and finally a template indicating that this is a student image.'''

'''Image:''' Expression of Endometrial CD98 in implantation<ref name:"PMID20976164"><pubmed>20976164</pubmed></ref>
[[Image:Expression of Endometrial CD98 in implantation.png|thumb|center|alt=Alt|Expression of Endometrial CD98 in implantation]]

'''2) Identify a protein associated with the implantation process, including a brief description of the protein's role (1-2 paragraphs).'''

A study has identified trophinin as a protein important to the adhesion implantation process. It is believed to be a single intrinsic protein that spans the membrane due to hydrophobic tendencies. This molecule can adhere without the aid of calcium unlike many cell adhesion molecules. Trophinin molecules bind with other trophinin molecule in trans structure on the cell surface. Immunostaining showed that antigens specific to the trophinin molecule can be found in both trophoblast cells and in the maternal epithelium near implantation sites of the embryo. The protein has been found to be encoded in the short arm of the X chromosome. It is also present in the mouse, sheep and bovine, along with monotremes and marsupials. It appears that the binding of the trophectoderm (consists of trophoblasts and is the connection between the blastocyst and the maternal cells) is essential to invasion and proliferation of cells. In embryonic cells trophinin induces and promotes invasion and proliferation. In maternal cells the same protein promotes apoptosis (controlled cell death) so as to allow the acceptance of the embryo. Therefore it is a dual signalling molecule. <ref name="PMID22717627"><pubmed>22717627</pubmed></ref>

===Reference===
<references/>

==Lab 3 Assessment==

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

The gestational age refers to the time since the last normal menstruation period<ref>Moore, K.L., 2011 ''The Developing Human'' 9th ed. W.B. Saunders</ref>. Whereas post-fertilisation age is calculated from the time of fertilization. There can be confusion between the terms espcially as gestational age is two weeks longer than post-fertilisation age<ref name:"PMID"15520122"><pubmed>15520122,</pubmed></ref>. Although in itself the term gestation age is confusing as there is no actual conceptus in until fertilisation but it is accepted by clinicians through widespread use<ref name:"PMID16006453"><pubmed>16006453</pubmed></ref>. As exact post-fetilisation age would be difficult to determine gestational age is used clinically. In assisted reproduction cases post-fertilisation age can be accurately determined but 2 weeks are generally added to age for ease of understanding<ref name:"PMID"15520122"><pubmed>15520122,</pubmed></ref>.

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

Somites form the dermis of the dorsal epithelium, skeletal muscles and some connective tissue, specifically, the vertebrae and ribs.<ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Paraxial Mesoderm: The Somites and Their Derivatives. Available from: http://www.ncbi.nlm.nih.gov/books/NBK10085/</ref>

===References===
<references/>

==Lab 4 Assessment==
'''1) Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.'''
Prenatal placental biopsy an invasive diagnostic technique for genetic abnormalities (such as trisomy 21) in the fetus. A karyotype is constructed allowing analysis of the chromosomes. It is used in the second and third trimester of pregnancy to confirm suspected malformations. Placental biopsies are sonographically guided<ref name:"PMID2712602"><pubmed>2712602</pubmed></ref>.
Chorionic villus testing is another invasive technique carried out transcervically in the first trimester to detect inherited disorders such as haemophilia <ref name:"PMID22250892"><pubmed>22250892</pubmed></ref>

'''2) Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''
Mesenchymal stem cells derived from the human umbilical cord have been used as a therapeutic treatment for neuromyelitis optica. Neuromyelitis optica is an autoimmune inflammatory disease that effects the optic nerve and spinal cord. Stem cells have been seen to provide differentiation potential to neural cells, secrete necessary factors and help regulate immunological function.
Five patients were treated with stem cell injections and then monitored for 18 months to analyse the effects both adverse and any improvements. Four out of the five patients gained some relief following treatment. Signs and symptoms decreased and the frequency of relapse was lessened. The neurological lesions also decreased in volume and severity as seen by MRI. The paper summarised that human umbilical cord stem cells were an appropriate therapy technique<ref name:"PMID22873728"><pubmed>22873728</pubmed></ref>.

===References===
<references/>

==Lab 7 Assessment==
'''1. (a) Provide a one sentence definition of a muscle satellite cell'''

Muscle satellite cells are progenitor cells and are involved in muscle growth and repair as they can induce regenerated muscle and additional satellite cells<ref name:”PMID12757751”><pubmed>12757751</pubmed></ref>

'''(b) In one paragraph, briefly discuss two examples of when satellite cells are activated.'''

A study investigating exercised induced satellite cell activation in skeletal muscle of growing and mature rats concluded that satellite cells are activated by acute sessions of prolonged eccentric exercise. It also concluded that exercise affected the proliferation of young mitotically active satellite cells<ref name:”PMID3693217”><pubmed>3693217</pubmed></ref>. Satellite cells are also activated when damage occurs. A study indicated that two variants of the IGF-I gene are necessary for activation of satellite cells. The study examined induced lesions to the anterior tibialis muscle of rats. The results showed that one variant of the gene which gives rise to a growth factor, MGF, is initially produced after injury and it activates satellite cells then IGF-IEa is expressed to maintain the repair process <ref>M Hill1, A Wernig, G Goldspink '''Muscle satellite (stem) cell activation during local tissue injury and repair''' Journal of Anatomy:2003, 203(1);89-99</ref>

'''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.'''

In a study involving 12 human patients suffering from spinal cord injuries a section of the vastus lateralis muscle was biopsied at 3 intervals within the first 6month following injury. From 6-24 weeks after injury they showed 27-56% atrophy of Type I, IIa and IIax+IIx fibers. There was increased conversion between muscle types, type IIa decreased and type IIax+IIx increased. However there was little change in proportion of tpye I fibers during this period<ref name:"PMID9887150"><pubmed>9887150</pubmed></ref>

===Reference===
<references/>

==Lab 8 Assessment - Peer Review==
===Vision===
The layout of the page is relatively good. If anything it appears little too image heavy at the moment. On the note of images, the referencing is good but don't forget to include the student template note with each image. The inclusion of some student drawn images in great to see but it might be an idea to make the labels larger as they are hard to read. The use of subheadings is great, a really logically well set out page. The references need a bit of work, some are spread sporadically throughout the page and some in the references section just list the URL along with the error on reference number 13.

The introductory is brief but alright. However the first two images are largely similar, not sure why both need to be included. Perhaps if possible it would be nice to link each of the main anatomical bullet points you have listed in your introduction to their associated developmental paragraph further down the page.

The History of development is coming along nicely but perhaps would be easier to read if it was in the format of a table. Also the Atlas of the Development of Man needs to be properly referenced with the author in the reference section. It would be nice to have some information relating to the pictures uploaded in this section.

The section on Development is well done and it is interesting to look at the individual development of each structure. It might be an idea to include some more references to when each structural development occurs. Current Research really needs some more content. The glossary is a nice addition and helpful.

===Somatosensory===
This page has made good use of subheadings ensuring that the main topics are easily accessible from the contents box. The project appears a little text heavy, it may help to include some other images. Also don't forget to add the student template note on the student drawn image. The reference list at the end is not particularly extensive. Perhaps this can be worked on by collecting the loose references in the text and adding them to the final reference section. Overall some sections of the page seem to have little to with embryology and more focused on adult function.

The introduction, while good, seems to lack any original voice, rather seeming to consist almost entirely of research done by others. The referencing in this section is also confusing with (Lagercrantz, Hanson, Evrard & Rodeck, 2001) being listed before any text. Referencing in this format also makes the page seem like a report or essay rather than a web page. There is also mention of a picture that does not exist. The historic section is brief and rather hard to digest as it is just a chunk of text. Perhaps putting this information into a table and developing it a little would help here.

The section on Central Somatosensory Differentiation was particularly well done. The inclusion of the student drawn image making all the difference. The general structure of this section is also commendable.

The subtitles "Touch", "Pain", "Heat/Cold" and "Pressure" are somewhat abrupt and don't particularly indicate what the section is discussing. This section in particular could do with the addition of some images. The information under Touch could perhaps be a little more heavily researched but is generally well written. Breaking the Pain section into some smaller paragraphs could be useful. The Hot/Cold and Pressure sections are well done excepting the random references to some articles.

Current research section could do with some more information. There are several words throughout the content that could do with being linked to an explanation in the glossary such as the "dorsal column-medial lemniscal system". The external links section is a good addition but it might be helpful to explain more clearly what each links to, especially the last three.

===Taste===
Initially the page seems to have a good balance between text and diagrams/photographs. However the figures included are not properly labelled once you click on the file and some of them don't appear to have any copyright information included. Some of the pictures could do with being a bit smaller as they take up a large proportion of the page. The student drawn image of the tongue is particularly impressive but does still need to have the student template included. The references seem limited in comparison to other groups perhaps suggesting a lack of depth or variety of research. There also appears to be a coding problem relating to reference number 5. The general layout and use of subheadings is great. It may be useful to link the words in the glossary to their occurrence in the text.

The introductory paragraphs are very well written. They are easy to understand and interesting and give a good overview of how taste functions. Similarly the section on taste map is well written clearly explaining the neurological factors associated with taste. However the presence of the picture in isolation is confusing as it is representing an the old method of taste association. Perhaps this would be resolved if a diagram of the newer taste map was also included. Also you say that the old taste map has been disproved by recent research but that research is not referenced. In fact it appears that very little of that section is referenced. The section on cortical areas is well done.

The timeline of developmental processes is good, the table an easy visual format and the information concise and effective. The only point of contention would be the direct quote in Wk8-9 which seems out of place in comparison to the remainder of the entries which are nicely paraphrased. The history section is similarly well done being extensive and comprehensive. That is excepting some Pub Med references which are just placed in the text rather than in the reference list at the bottom. While interesting and well written the part detailing the Adult Tongue and Taste Buds seems out of place in a embryology course.

The sections on the effect of gene expression on the formation of taste abnormalities and current research are good. However it may be useful to put the information regarding each picture as a caption rather than plain text.

It will be interesting to see what is put in the section "Image Gallery"

===Abnormal Vision===
Your introduction is relatively well written and the brief explanation of new terms such as microphthalmia was particularly useful. Perhaps it would be possible to break the text into two paragraphs to make reading easier.
It is really good to see a section included about normal eye development as it provides a basis of understanding for the remainder of the page. Concise and to the point and not too complex, it's great. Only suggestion would be to place it in a table perhaps with each Carnegie stage a new entry.

Layout of abnormalities is very logical covering the main areas of developmental abnormalities. However it is slightly confusing that immediately under the title Abnormal Lens Development more information on normal development is given. Allocating the defects to their associated individual genes is good but perhaps instead of a dotpoint a subheading would be of more use. The actual information is clearly and effectively written. The inclusion of the pictures clearly illustrates the abnormalities but their placement is a little odd. Perhaps they are too large. The captions on the pictures are appropriate and the pictures are appropriately referenced and it is great that the link to the picture contains more information.

Under the title "Ocular Manifestations" perhaps indicate what the two sections are, just so the following on sections make sense and don't appear disjointed. The sections on the genetic caused abnormalities is fascinating and very well written. The timeline included in the information about Leber Congenital Amaurosis is particularly interesting. The spacing in the section on genes associated with Anophthalmia and Microphthalmia appears slightly strange. The figures included are particularly illustrative and appropriate. Similarly the section on environmentally caused abnormalities is really well written and interesting.

Perhaps a more extensive section on current research could be included. If possible, link the words in the glossary to where they appeared in the text. This is the coding if you don't have it [[#Glossary|'''Words for Glossary''']]. Just add that in place of the word when you first mention it in the text. The citing and referencing is really well done. It also shows a great depth of research. The figures/photographs so far included are brilliant but the inclusion of a student drawn diagram somewhere if possible would be effective. Also try and fix the general layout of the project, possibly including some more subheadings. In general the content relates to the the course and is pitched at an appropriate level. Hope this helps.

===Hearing===
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.

==Lab 9==
'''1) Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

Hes1 is a target gene associated with notch signalling (a type of cell signaling pathway). It affects the proliferation and differentiation of progenitor cells. mic lacking the Hes 1 gene were observed to analyse the genes involvement in thyroid analyses. In a normal mouse the gene was expressed after E9.5. Hes1 lacking mice presented a smaller thyroid surface area at all stages and the fusion of the median anlage and ultimobranchial bodies was significantly delayed. It was suggested that the Hes1 gene is important for control of final number of thyrocyte and C-cell progenitors and ensuring adequate differentiation and endocrine function of these cells<ref name = "PMID21364918"><pubmed>21364918</pubmed></ref>.

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

Teeth form from the ectodermal layer of the oral cavity in association with the surrounding mesoderm. Specialised ectodermal cells termed ameloblasts secrete enamel. Mesenchymal mesoderm is responsible for other dental structures. Other specialised cells involved in tooth formation include odonoblasts and cementoblasts.<ref>John F. Neas, 2002 ''Human Anatomy Fourth Edition'', Chapter 4, Benjamin Cummings. Sourced from: http://cwx.prenhall.com/bookbind/pubbooks/martini10/chapter4/custom3/deluxe-content.html </ref>

===References===
<references/>

2012 Group Project 4

2012-10-05T08:31:39Z

Z3374215: /* Cribiform plate */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
|[[File:Vomeronasal Organ position.jpg|thumb|right|200px|alt=Alt|''Vomeronasal Organ position''']]

Discovery of [[#Glossary|'''Vomeronasal organ''']] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|'''hypogonadism''']] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name="PMID15836430"><pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|'''epiblast''']], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of [[#Glossary|'''ectoderm''']]<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|'''cribriform plate''']]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia and midline anatomic defects) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for revealing the large number of genes involved in odour reception. <ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|300px|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The [http://www.example.com nasal cavity] is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
As highlighted in the diagram of the "nasal cavity", the olfactory epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.
<ref name="Neuroscience, 2nd edition">[Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates; 2001. Available from: http://www.ncbi.nlm.nih.gov/books/NBK10799/</ref>

==== Olfactory Epithelium ====

[[File:Olfactory_epithelium.jpg|380px|thumb|right|Olfactory Epithelium]]

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
As indicated in the diagram, [http://www.ncbi.nlm.nih.gov/books/NBK10896/ olfactory epithelium] also contain basal/stem cells which give rise to olfactory receptor cells. Current research indicate that these basal cells continue to proliferate and differentiate into receptor cells throughout the life of a person. <ref name="PMID7143026"><pubmed>7143026</pubmed></ref>.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.<ref name="PMID17468753 "><pubmed>17468753 </pubmed></ref>.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined. The olfactory bulb is essential for olfaction as it transmits information from the olfactory epithelium and up to the brain. The bulb receives input from olfactory nerves which constitutes the axons of olfactory receptor neurons. <ref name="PMID12951145 "><pubmed>12951145</pubmed></ref>.

Structures known as glomeruli form by a number of olfactory axons joining together such that each glomerulus obtain information from olfactory neurons which have the identical odour receptors. These glomeruli structures are also surrounded by dendrites belonging to mitral cells which transmit electrical signals to the olfactory cortex in the brain.<ref name="PMID16269360"><pubmed>16269360</pubmed></ref>.

====Cribiform plate====

The cribiform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groove allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha. If the cribriform plate happens to get fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose. <ref name="PMID11226964"><pubmed>11226964</pubmed></ref>.

== Normal Function ==

===Olfactory Signal Transduction===

[[File:Olfaction_signal_transduction.JPG|160px|thumb|right|Signal Transduction and Processes in Olfaction]]

Olfactory Signal Transduction is initiated by any substance that emit molecules known as odours. The [http://www.youtube.com/watch?v=dIDBG-UPRUI&feature=related| Signal Transduction] is dependent upon the dissolving of these odours in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors so that chemical compounds are converted into electrical signals. The transformation into electrical signal is essential for signal transduction for the brain to perceive the initial odours as smell. <ref name="PMID18066954"><pubmed>18066954</pubmed></ref>.

When odour molecules bind to receptors in olfactory epithelium, a G protein coupled receptors known as Gαolf and Gβγ are activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP (cAMP). As highlighted in the diagram B of "Signal Transduction and Processes in Olfaction", the receptor cells in the olfactory epithelium ascend towards the olfactory bulb, enabling cAMP binding to cation channels and as a result allow for an influx of sodium and calcium ions through the binding to and opening of cyclic nucleotide gated ion channel. <ref name="PMID19652915"><pubmed>19652915</pubmed></ref>. The main effect of ion entry into the cell is depolarisation, and activation of chloride channels resulting in greater depolarisation by the efflux of chloride ions. If the depolarization in the cell is great enough, an action potential is generated on the axon of the receptor cell and transferred to the brain through the olfactory bulb.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref><ref name="PMID21041441"><pubmed>21041441</pubmed></ref>.

Similar to other G-protein mediated pathways, the olfactory sensory neuron is exposed to negative feedback by the cAMP cascade activated by odours. The negative feedback loop has been discovered to be responsible for the adaption of odours and deactivation of response after exposure for a certain period of time. <ref name="PMID19804753"><pubmed>19804753</pubmed></ref>.

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
* Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982">
<pubmed>15893982</pubmed></ref>

* Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

||
* All five facial swellings form initially surrounding the stomodeum.

* The [[#Glossary |'''frontonasal prominence''']] is the facial swelling which gives rise to [[#Glossary | '''olfactory placodes''']]. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>.

An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. Mesencephalic region produced neural crest cells which contributed to the frontonasal mass.<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>

* These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

* Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

* Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref name="PMID15454774"><pubmed>15454774</pubmed></ref>
||
[[File:week4.jpg|200px|thumb|right|Embryo at week 4]]
|- bgcolor="#89CFF0"
|''Week 5'' ||
* Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

* As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

* The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit as the face folds, dividing the frontonasal prominence into the lateral and medial nasal processes.These pits deepen as the surrounding mesenchyme proliferates to form '''primordial nasal sacs''' which grow dorsally but remain ventral to the forebrain. <ref name="PMID15454774"><pubmed>15454774</pubmed></ref> These sacs are separated from the oral cavity via the '''oronasal membrane'''.

* '''Glial cells''': Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref>

||
[[File:Week5.jpg|200px|thumb|right|Embryo at week 5]]
|- bgcolor="#BCD4E6"
|''Week 6'' ||

* FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

* Slit2 and Robo3 have been found to play a role in GnRH migration to the hypothalamus in mice embryological development via the vomeronasal axons.<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

* CSF-1R is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

* Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus.<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>

||
* '''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

* The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and [[#Glossary |'''nasal septum''']].<ref name="PMID438867"><pubmed>438867</pubmed></ref>

* The oronasal membrane ruptures by the end of this week, allowing communication between the nasal and oral cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* '''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
The superior, middle, and inferior nasal conchae develop as the lateral walls of the nasal cavities proliferate and so elevate.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref name="PMID15454774"><pubmed>15454774</pubmed></ref>

* '''Vomeronasal Organ Primordium''': Visible as epithelial swellings on the lower medial aspect of the nasal pit.<ref name="PMID9712194"><pubmed>9712194</pubmed></ref>. The anterior part can be seen as an indentation and the posterior part can be seen as continuous epithelium with the nasal septum. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* [[#Glossary |'''Vomeronasal Organ''']]: The VNP's are no longer visible but are instead in the form of bilateral tubes with well delineated lumens, that open anteriorly into the nasal cavity.<ref name="PMID11117628"><pubmed>11117628</pubmed></ref> The VNO epithelium is thicker than respiratory epithelium up until 12 weeks when the respiratory epithelium overtakes in thickness<ref name="PMID11117628"><pubmed>11117628</pubmed></ref>. The medial sides of the VNO's proliferate into thicker, microvillous sensory epithelium while the the lateral sides are thinner, receptor-free, ciliated epithelium. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

||
[[File:Week6.jpg|200px|thumb|right|Embryo at week 6]]
|- bgcolor="#89CFF0"
|''Week 7''||
* BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

* ''Neurog1'' and ''Neurog2'' play a role in signalling the specialisation of the olfactory epithelium and olfactory bulb neuron morphogenesis.<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>

* ''Pax6'' plays a role in early neurogenesis of the olfactory bulb.<ref name="PMID8756438"><pubmed>8756438</pubmed></ref> Non-neuronal cells such as sustentacular cells, basal cells and Bowman's glands express this transcription factor.<ref name="PMID8756438"><pubmed>8756438</pubmed></ref>

* Similar results have been found with Olf1 transcription factor expressed in olfactory sensory neurons(OSN's).<ref name="PMID8756438"><pubmed>8756438</pubmed></ref> It has been found to play a role in the development of the odorant signal transduction cascade which determine the final pheontype of the OSN's.<ref name="PMID8756438"><pubmed>8756438</pubmed></ref>
||
* '''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla.
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* '''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse to form the primary palate.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, [[#Glossary |'''Nasal fin.''']]<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* '''Secondary Palate''': Formed as the two palatine shelves extend medially and fuse at the midline at the primary palate.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The lining of the olfactory placode differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

- '''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

- '''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

- '''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

* At the end of the 7th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated [[#Glossary |'''cribriform plate''']]. <ref name="PMID15454774"><pubmed>15454774</pubmed></ref>

* [[#Glossary |'''Olfactory bulb''']] growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* [[#Glossary |'''Olfactory nerve''']] formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.<ref name="PMID11117628"><pubmed>11117628</pubmed></ref>
As a result, the CNS olfactory tracts look stalk-like.

* '''Olfactory nerve''': the '''olfactory tract''' and bulb together.

* By this stage the olfactory nerve is divided into a medial and lateral plexus. The medial plexus receives the VNO axon strands which are directed towards the caudal part of the olfactory bulb. Meanwhile the lateral plexus receives axon elongation from the olfactory epithelium and is directed towards the lateral edge of the olfactory bulb. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* Migration of Gonadotropin Releasing hormone along the vomeronasal nerve between weeks 6 to 8- plays a part in hypothalamus development.<ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
[[File:Week7.jpg|200px|thumb|right|Embryo at week 7]]
|- bgcolor="#BCD4E6"
|''Week 8/Fetal development''||
* BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
* '''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* '''VNO:''' At this stage, the number of ciliated VNO epithelial cells increases into the late fetal period whilst the number of receptor cells decreases. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>
The degeneration of the VNO is noted by the closure of the duct and formation of a cyst like structure in the nasal septum. However, in most adults, the duct is left opened to a certain degree.<ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
||
[[File:Stage 22 image 057.jpg|200px|thumb|right|Embryo at week 8]]
[[#Anatomy of the Olfactory System |'''Also see normally developed sensory structures of olfaction''']]

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann Syndrome|'''Kallmann Syndrome''']]. At present, these conditions are the most commonly recognised congenital conditions contributing to abnormal olfactory function.

------

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by narrowing or complete obliteration of the nasal aperture by a bony or membranous occlusion.<ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref> This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance.<ref name="PMID881923"><pubmed>881923</pubmed></ref>
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. The table below displays models which have been proposed to explain how choanal atresia may occur in the developing human.

<table>
{| width=100%
|-bgcolor="#FF9900 "
| width=20%|'''Risk Factor Model'''
| width=80%|'''Description'''
|-bgcolor="#FFFF99"
| ''' Embryonic'''
| Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence":
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter<ref name="PMID19328897"/>
* Abnormal persistence of mesoderm, resulting in adhesions in the nasochoanal region<ref name="PMID19328897"/>
* Misdirection of neural crest cell migration <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>
|-bgcolor="#FFCC66"
| '''Genetic'''
|
* A study <ref name="PMID3679682"><pubmed> 3679682</pubmed></ref> reported that 30% of children with choanal atresia had '''CHARGE Syndrome''' which stands for: Coloboma, Heart defect, Atresia Choanae, Retarded Growth and development, Genital hypoplasia, Ear anomalies or deafness.<ref name="PMID19328897"/>
* CHD7 gene on chromosome 8q12.1 found in 64% of CHARGE syndrome patients though its function is unknown. <ref name="PMID16155193"><pubmed>16155193</pubmed></ref>
|-bgcolor="#FFFF99"
| '''Molecular'''
|
* '''Thionamides and Hyperthyroidism''': There have been studies which have reported an increased incidence of choanal atresia in babies of hyperthyroid mothers treated with thionamides.<ref name="PMID3688031"><pubmed>3688031</pubmed></ref><ref name="PMID9450891"><pubmed>9450891</pubmed></ref><ref name="PMID18698631"><pubmed>18698631</pubmed></ref> The majority of hyperthyroid mothers with babies with choanal atresia had elevated levels of stimulating antibody for the thyrotropin receptor.<ref name="PMID19328897"/> Human studies and animal models have shown that elevated thyrotropin alters the expression of the fibroblast growth factor (FGF), FGF receptors and angiogenic factors which may play a role in development of choanal atresia.<ref name="PMID12746216"><pubmed>18698631</pubmed></ref><ref name="PMID11397875"><pubmed>11397875</pubmed></ref> However, further research is required in order to determine the exact mechanisms linking thionamides, hyperthyroidism and choanal atresia.

* '''Retinoic Acid''': Retinoic acid is the product of vitamin A metabolism by retinaldehyde dehydrogenase (Raldh).<ref name="PMID19328897"/> Mouse models showed that an absence of Raldh caused choanal atresia, resulting in respiratory distress and death of Raldh3 knockout mutants at birth.<ref name="PMID14623956"><pubmed>14623956</pubmed></ref>
|}
</table>

====Clinical Features====

[[File:Choanal atresia computed tomography 01.jpg|300px|thumb|right|Computed Tomography of Choanal Atresia]] Neonates are obligate nose breathers, hence neonatal nasal obstruction as seen in choanal atresia is a serious deformity.<ref name="PMID11232465"><pubmed>11232465</pubmed></ref> In order to avoid severe hypoxia and death, immediate diagnosis and intervention are key.<ref name="PMID11232465"/> The severity of the clinical features of choanal atresia depends on the whether the obstruction is unilateral or bilateral.<ref name="PMID19328897"/>

'''Bilateral'''
* At birth present with ''asphyxia neonatorum'': pathological changes caused by hypoxia from affected respiration. This is a medical emergency requiring an oral airway tube or intubation then immediate surgical intervention <ref name="PMID19328897"/><ref name="PMID12567078"><pubmed>12567078</pubmed></ref>
* Obvious airway obstruction <ref name="PMID19328897"/>
* Stridor, a harsh vibrating sound when breathing <ref name="PMID19328897"/>
* Paradoxical cyanosis: cyanosis (blue appearance from deoxygenated blood) is present in the infant at rest but improves with exertion such as crying <ref name="PMID19328897"/>

'''Unilateral'''
* Not as life threatening as bilateral choanal atresia; more often diagnosed in childhood than in infancy <ref name="PMID19328897"/><ref name="PMID12567078"/>
* Mucoid rhinorrhea, constant mucous fluid discharge from nose <ref name="PMID19328897"/><ref name="PMID12567078"/>
* Dysosmia: distorted olfaction <ref name="PMID12567078"/>
* Obstructive sleep apnoea <ref name="PMID12567078"/>

------

===Kallmann Syndrome===
====Introduction and Epidemiology====
[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|500px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]Kallmann syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell.<ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref> The incidence of Kallmann syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people<ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio. <ref name="PMID21682876"><pubmed>21682876</pubmed></ref> [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves. <ref name="PMID21682876"/> Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann syndrome can be inherited as an X-linked recessive, autosomal dominant or autosomal recessive trait.<ref name="PMID21682876"/>

====Pathophysiology====
The olfactory bulb (OB) is the first neuronal checkpoint for olfactory information.<ref name="PMID12007408"><pubmed>12007408</pubmed></ref> The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex.<ref name="PMID12007408"><pubmed>12007408</pubmed></ref> During embryonic development, axons from the olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells. <ref name="PMID12007408"/> The axons of these neurons form the olfactory tract. In Kallmann syndrome, the OB is abnormal in structure or not present; coupled with neuronal migration failures, olfactory signals from the environment are prevented from being transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

'''Genetic Factors'''
In Kallmann syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann syndrome can be X-linked , autosomal dominant or autosomal recessive.<ref name="PMID21682876"/> To date, mutations in six genes and the proteins they encode (see table below) have been attributed to Kallmann syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis of Kallmann Syndrome are found to have a mutation in these genes.<ref name="PMID20949504"><pubmed>20949504</pubmed></ref> Note that CHD7 can also be mutated in Kallmann's syndrome patients, though these individuals tend to have additional features that are part of the CHARGE syndrome phenotype described in the section on [[#Choanal Atresia|'''Choanal Atresia''']].<ref name="PMID19021638"><pubmed>19021638</pubmed></ref>

<table>
{| width=100%
|-bgcolor="#FF9900"
| width=9%|'''Gene'''
| width=20%|'''Mode of Inheritance'''
| width=50%|'''Role in Kallman’s Syndrome'''
|-bgcolor="#FFFF99"
| '''KAL1'''
| X-linked recessive
| KAL1 normally encodes glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb.<ref name="PMID1913827"><pubmed>1913827</pubmed></ref> Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from the OB towards the piriform cortex; this is through patterning of the mitral and tufted cell axons to the olfactory cortex.<ref name="PMID12007408"><pubmed>12007408</pubmed></ref> Consequently, in the absence of anosmin-1, Kallmann syndrome arises due to abnormal olfactory neuronal development.<ref name="PMID12007408"/> Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann syndrome.<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>
|-bgcolor="#FFCC66"
| '''FGFR1 (KAL2)'''
| Autosomal-dominant <ref name="PMID20117945"/>
| FGFR1 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration.<ref name="PMID20117945"/> <ref name="PMID12627230"><pubmed>12627230</pubmed></ref> When absent, Kallmann syndrome arises due to agenesis or digenesis of the olfactory bulb and failure of GnRH neuronal development and migration.
|-bgcolor="#FFFF99"
| '''FGF8'''
| Autosomal-dominant <ref name="PMID20117945"/>
| Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation. The absence of FGF8 produces a similar phenotype to the KAL2 mutation as the receptor is not activated.<ref name="PMID20117945"/>
|-bgcolor="#FFCC66"
| '''PROKR2 (KAL3)'''
| Monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID20389090"><pubmed>20389090</pubmed></ref><ref name="PMID18826963"><pubmed>18826963</pubmed></ref>.
| Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling.<ref name="PMID18826963"/> However, the exact role in Kallmann syndrome has yet to be clarified.<ref name="PMID18826963"/>
|-bgcolor="#FFFF99"
| '''PROK2 (KAL4)'''
| Hypothesised to have mendelian autosomal recessive transmission in addition to oligogenic transmission.<ref name="PMID20389090"/>
| Encodes the PROKR2 ligand.<ref name="PMID18826963"/> When PROK2 mutated, the ligand is not expressed preventing prokineticin receptor-2 activation; this produces similar effects to PROKR2 abnormalities.

|}
</table>

====Clinical Features====

Kallmann Syndrome has the classical hypogonadotropic hypogonadism (HH) feature of an absence of puberty but is distinguished from other HH syndromes by an affected sense of smell<ref name="PMID22882983"/>. There exists additional characteristics that are not specific to Kallmann syndrome but may aid in correct diagnosis of this particular HH<ref name="PMID22882983"/>. The following characteristics of Kallmann syndrome may or may not be present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* Cryptorchidism: Failure of one or both testes to migrate into the scrotum during male foetus development<ref name="PMID16932275"/>
* Gynaecomastia: The development of abnormal mammary glands in males characterised by enlarged breasts<ref name="PMID16932275"/>
* Amennorhoea: the absence of menstruation, in females<ref name="PMID16932275"/>

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell. <ref name="PMID16932275"/> Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']]. <ref name="PMID16932275"/>
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification
* Unilateral renal [[#Glossary |'''aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* Pes cavus: Also called clawfoot, refers to a deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. <ref name="PMID16932275"/>
* Neurological symptoms
** Synkinesia: Patients can conduct voluntary movements, however, with accompanied involuntary muscular movements.
** Abnormalities in eye movement
** Cerebellar ataxia: Reduced control over muscle coordination arising from defects or damage to the cerebellum.
** Evoked horizontal nystagmus: fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.
** Sensorineural deafness
** Spatial attentional abnormalities
** Spastic paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>

===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism. <ref name="PMID11052640"><pubmed>11052640</pubmed></ref> Instead, doctors often dismiss Kallmann syndrome as constitionally delayed puberty. <ref name="PMID11052640"/> Other differential diagnoses include potential presence of hypothalamic or pituitary tumours.<ref name="PMID11052640"/> Due to the varied phenotype and genotype of Kallmann, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests.
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH.
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics.<ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann syndrome, olfactory bulb is either not present or not fully developed.<ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmanb syndrome; however, negative result does not rule out possibility of the syndrome.<ref name="PMID20949504"/>
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation.<ref name="PMID20949504"/><ref name="PMID11052640"/><ref name="PMID11531922"/>
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
[http://www.ncbi.nlm.nih.gov/pubmed/21543621 Forni PE et al.]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]][http://www.ncbi.nlm.nih.gov/pubmed/21943152 ''The dual origin of the peripheral olfactory system''] also investigated the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
[http://www.ncbi.nlm.nih.gov/pubmed/22906231 Shaker T. et al.] published a paper in August this year looking into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular section of the research looked to determine whether Neurog1 and Neurog2 were required for olfactory bulb development. A loss-of-function technique was utilised to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
[[File:Absence_of_CSFR1_Impacts_Normal_Development_of_Brain_Architecture.jpg|200px|thumb|left|'''Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development'''- Absence of CSF-1R results in perturbed brain architecture.]]A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R in +/+ mice showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression at all. Moreover, cell counts showed that in -/- mice, the numbers of microgliadeclined within three weeks of birth. The microglia depletion in -/- mice was accompanied by abnormal structural integrity of the brain: there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an important role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in external structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of the enlarged cerebrospinal fluid compartment impinging on the olfactory bulb's normal growth. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1R is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
The LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, the olfactory sensory neurons (OSNs) and the vomeronasal sensory neurons in the developing human (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects such as those seen in Kallmann syndrome.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cribiform Plate''': The inferior surface of the ethmoid bone which roofs the nasal cavities.

'''Ectoderm:''' The outermost layer of the trilaminar embryo. Differentiates to form structures including the epidermis and neural tissue.

'''Epiblast:''' The collective term for embryonic mesoderm and ectoderm before differentiation

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Frontonasal Prominence''': An ectodermal expansive process that arises during the third week of embryonic development and forms the forehead and nasal bridge.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nasal Fin''': A plate-like ectodermal structure that forms between the medial and lateral prominences that thins to the form the oronasal membrane.

'''Nasal Septum''': Separates the left and right airways of the nose into nostrils. It is made up of the perpendicular plate of ethmoid bone, the vomer bone, cartilage and the crest of the maxillary and palatine bones.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Olfactory Placode''': A thickened area of ectoderm on the frontonasal prominence which contributes to the development of the olfactory sensory system.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones. A rudimentary organ in humans.

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

[http://kallmanns.org/ The Kallmann's Syndrome Organisation]

==Image Gallery==
<gallery>
Image:Vomeronasal_Organ_position.jpg
Image:Nasal_placode_diagram.jpeg
Image:Olfactory_bulb_and_epithelium.png
Image:Olfactory_epithelium.jpg
Image:New_olfactory_bulb.jpg
Image:Choanal_atresia_computed_tomography_01.jpg
Image:Normal_Neuronal_Migration_into_the_Olfactory_Bulb_Compared_to_Kallmann's_Syndrome.jpg
Image:Neural_crest-derived_cells_in_the_embryonic_olfactory_epithelium.jpg
Image:Absence_of_CSFR1_Impacts_Normal_Development_of_Brain_Architecture.jpg
Image:week4.jpg
Image:week5.jpg
Image:week6.jpg
Image:week7.jpg
</gallery>

{{External Links}}

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

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{{2012Projects}}

Talk:2012 Group Project 4

2012-10-04T23:02:28Z

Z3374215: /* Progress of individual tasks and project queries */

{{2012GroupDiscussion}}

--[[User:Z8600021|Mark Hill]] 09:59, 18 September 2012 (EST) This is a recent review on smell. http://jcb.rupress.org/content/191/3/443.full JCB content allows reuse.

Not for reuse but good reading - [http://www.ncbi.nlm.nih.gov/books/NBK55980 The Neurobiology of Olfaction]

==Introduction==

Hey Team... I was just wondering if we had come to a conclusion as to what image we wanted to place at the top of the page?? Please get back to me asap.

[[User:Z3333427|Z3333427]] 14:37, 27 September 2012 (EST)

==Signal Transduction==

Have anyone found an informative image we can use for this section

[[User:Z3333427|Z3333427]] 10:37, 2 October 2012 (EST)

--[[User:Z3333038|Z3333038]] 10:44, 2 October 2012 (EST)Yes - http://jcb.rupress.org/content/191/3/443.full on this page. Mark says JCB allows content to be reused, just reference it.

==Group evaluation==

The project page was exceptional, there is a fine combination of text and images and the images are well integrated with the presented information. I particularly like the inclusion of a hand drawn histological section embedded within the table of historical findings. Perhaps this could also be done in the next table about the developmental timeline. As it stands, this table, while detailed in its wording may be difficult to understand as there are no diagrams to show the differentiation in visual terms, from week to week.

The clinical features, anatomy, and pathohophysiology were excellent. There is not much more to say. All of the diagrams were properly cited with correct copyright information. The CT scan was also interesting to look at.

One aspect that hasn’t been touched on is future research. The current research section was very detailed and explained the significance of each new finding however as is the nature of research, there are always gaps left in our understanding or further questions that need to be resolved as a result of new information. A brief section on this would give the project more depth as it would show a level of critique rather than simply the presentation of fact.

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

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

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

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

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

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

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The work needs to be spell checked before you submit it, make sure you get all your grammar right as well. I think you should add more to your introduction, and make it a little simpler, easier to follow. Also throughout your project you tend to use a lot of long paragraphs, especially in the current research section.

Though the developmental timeline that is set up is very detailed, it can be a bit hard to follow and a little confusing. There is too much text and no pictures at all to help demonstrate what is being said about the development. The ratio of images to text in the anatomy and abnormalities sections however is very good and makes it more interesting to read.

It’s good to see that you have some external links put up on the page and also that you’ve used quite a few references to do your research rather than just a few.

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WOW! I really can’t come up with anything bad to say about this wiki.
Text and image are nicely balanced.
Developmental timeline was very easy to follow and succinct which is always nice.
It was good to have research images alongside hand drawn images.
Diagnosis and treatment sections may need some expantion.
List of references current and varied – always good to see.

All in all this was a very good project and congrats of the good work. Keep it up.

Good luck with the rest ☺

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

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

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

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

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

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

- Current research is well put together

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

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The introduction was very interesting to read - 1000 genes related to olfactory system is amazing. The introduction isn't too long which is great. However, it would be good to include in text citations. Where did you get your information from?

The history section will look better if it was put into a table.

The 'Timeline of Development process' is excellent because it clearly presents so much information with respect to the time the differentiations took place. I can't wait to see the images though because some of the concepts were hard to understand without visual aids. For example, 'specialized areas in rostrolateral regions of head of olfactory placodes' - where is that on the embryo?

The normal function section was short. This is nice to see because this project is about development, not about the function. It would be good to include a diagram of the signaling pathway in this section, just to make it interesting.

The structure section needs a bit more information. Maybe put the olfactory bulb image in this section as it relates more to structure. You can also put some images of the cribiform plate in here too.

Abnormality section on Kallmann's syndrome was very well written. It had lots of detail, presented clearly in point form. Can you describe some of the other diseases in just as much detail as well? It just seems like Kallmann's syndrome is the main disease and there's not a lot of focus in other abnormalities.

In current research, 'the 'role of Odorant receptors' need to have some text and content in that section, not just the reference.

--[[User:Z3332863|Z3332863]] 16:58, 23 September 2012 (EST)

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Page is well structured. Tables and images break up the information nicely. Some of the images lack an in depth explanation of what they depict/represent when you click on them. I know for some of the images it might be hard, but i think it would make for a more thorough way of presenting the information.
Not to much a critique, but you spend a large amount of time and space on the abnormalities section. When combined with the current research section and the images, only about a third of your page is information on olfaction. An even less of it is on the actual embryology when considering the timeline of discoveries and introduction. Try and draw out the embryology section a little further, considering the context of the website and who would be visiting it.

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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).

Hope this helps!
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The introduction is quite small but very precise, indicating the function and the components of the olfactory system but maybe include one or two sentences in the introduction telling readers that it is actually about the development of the olfactory system, not just the function and components of it. After all, introduction is meant to show others what your project is about. The hand-drawn image there is very nice but maybe more information need to be provided other than just labelling parts of it. Along with the image, there are the important informations such as the copyright notice which is good to see.

The history of discoveries section is very well-researched but it will be easier to read if it was in a table. The timeline, i thought was very good because there are a lot of useful information about the development of olfaction which relates to the research topic. The developmental process is explained in quite simple terms but i notice some of the scientific terms in the timeline are not explained in the glossary, this makes it a little bit hard to understand the whole process. It is very interesting that a youtube link has been included in the structure section, this is really a good peer teaching but make sure you referenced the video correctly to avoid plagiarism. The section on Kallman's syndrome is quite interesting but the structure of that section is a bit messy, maybe try clarifying and tidy it up a lit. But i can see that a lot of research effort has been put into it which is good and the variety of resources used in the section is very broad. More images should be put here because right now, there is just a huge block of text in the section. Images will balance out the heavy text load and attract readers more.

The current research section contains a lot of useful information and it relates to the research topic well. Again, images should be put here because right now, there are just small blocks of text in the section without any images, this maybe a little bit boring for readers.

Overall, the project looks well-researched and relates pretty well to the research topic. The balance of the images and text still needs to be fixed but in terms of the text and information on the page, i think it is pretty sufficient and in-depth especially the timeline of development and current research section. There are some terms in the glossary which is good but maybe more terms should be added. The structure of the page is good, very easy to follow. There are a few external links which is always good to put there for anyone that are interested by the topic and want some further information about it. Referencing is good, there is only one minor citing error (no.7), but it should be easy to fix. Hope this helps :)

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The introduction provides a good overview to the topic and the associated images have all the appropriate referencing information.

The history section is interesting and well researched with good use of subheadings.

The timeline of development is very useful and informative however is quite text-heavy, some diagrams may be able to help here.

The anatomy and normal function sections don't add very much to the page, especially in terms of embryological development. Adding more to these sections may help.

The abnormalities section is good, with a lot of information on Kallmann's syndrome, however other abnormalities (if there are any?) could be included to expand this section.

The current research section contains a lot of information in a small amount of space. It is quite jargon-heavy although this might not be able to be avoided. The subheadings are good as they act to split this section into discrete units.

The glossary and external links are very good, and the references are extensive which is good.

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* '''Introduction''': The information is very interesting and provides a good overview of the olfactory system. The only improvement that could be made is clearly stating what content is going to be covered on this project page. Also, “The olfactory system are often ‘’’divide’’’ into a peripheral mechanism”
* '''History of Discovery''': This sections presents a good summary of each research paper, detailing a background of the researchers and the importance of each discovery. Well done!
* '''Time line of developmental process''': This section shows a good depth of research and provides detailed descriptions of each stage of development. However, the information provided is quite complicated and would not be easily understood by peers. This could be overcome by the use of labeled diagrams or hand drawn images, which I can see is yet to come. Overall this is a well done section, the colors draw the readers attention and I like the use of bolded text to highlight important information.
* '''Anatomy of the Olfactory System & Normal Function''': This provides a good amount of information seeing as the focus of the page is about olfactory development, not the function & final structure. The only improvement could be providing an explanation in the figure provided.
* '''Congenital Abnormalities''': This section is well organized and includes all relevant content. Very interesting to read.
* '''Current Research''': A well researched section and coverage of content. Each paper is summarized and the importance of each discovery is made clear. It would be nice to include a direct link to each article.

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For me this is one of the best projects of the 6 groups. It is extremely well researched, as seen through the extensive reference list. It is evident that the group has gone above and beyond, researching even more than required for the topic, or standards set by other groups, such as clinical approaches, and much information on current research.

I found that the formatting in the upper part of the page, specifically the section under the title ‘normal function’ was a bit awkward in relation to text and image positioning. It felt that it was not consistent with the flow of the rest of the page.
Also the first table may require an in-filled colour or even lines (can be a light or pale colour), just so each column and the single uploaded image is more defined and linked to the correct year/individual.

The ‘Choanal Atresia’ tomography image requires acknowledgement that the image was uploaded as part of a university assessment. However, really appreciated the breakdown of where the arrows were pointing and the relevance in relation to your specific topic.
Images for the tables need to be finalized and uploaded; ensuring that there is appropriate referencing, whether they are student drawn, or sourced from the literature.
Found that the student drawn diagrams were really detailed and easy to understand and appreciate. Each was also relevant to the topics, which they were linked/associated to.

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The introduction while small gives a great overview on what olfactory is. You could add a small overview on what the page is about to make this part a little longer.

I like your table on development however there is some information in the table which is missing references, you should see to that soon and add a reference. Some images in this section would be nice and if there are not going in the table then you might want to delete the image column.

The anatomy of the olfactory system is quite small; this part could possibly be added to your introduction.
Kallmann’s syndrome is done very well and is quite thorough and as a result the choanal atresia section looks lacking. I would suggest adding this to the bottom of your abnormalities section and if no more information is going to be added to the page maybe state that other abnormalities include - choranal atresia and then maybe an external link.

Current research section is quite detailed and I would not add anything else to this section. I did notice that Role of Odorant Receptors is just stated with a reference and no information. If nothing is to be added here I would just delete this heading.
--[[User:Z3220343|Z3220343]] 21:33, 25 September 2012 (EST)

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Group 4- olfaction

-numerous typos and syntax errors throughout. My favourite is "naval cavity"

-generally well explained and I like how you've used different formats for each section to keep it interesting

-this seems a bit random-

"SINUSES: A: EFFECT OF AMNIOTIC FLUID ON THE DEVELOPMENT OF OLFACTION IN THE FETUS (current research in the field):"

-I think the anatomy section should come before the developmental timeline just to put the developmental stages in context

-abnormal function is very comprehensive :)

-current research is great, it appears some quality research went into this

-excellent use of resources throughout, including your external links. I think you've covered everything well

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Introduction is sufficient for now, but it may be better if you add more details, and perhaps an image to support it. Maybe an image of the nose and its structural components labelled.

History of discoveries section is great so far. You gave succint information with references. You only have 1 useful image in this section, so it would be better if you add more images.

Developmental timeline is very well detailed and has appropriate refrencing, however more refernces need to be added for some of thee information. You also need to add images as that column is left blank so far.

Anatomy of the olfactory system needs more details and explain the structural components. The diagrams are good, but needs more description in the captions.

“Congenital Abnormalities” is very detailed, with appropriate referencing and good images. It would be good to add a few more images. Also, add more description in the “Computed Tomography of Choanal Atresia” image.

Current research section is very good so far. Perhaps adding a few more images to support the other articles would make it better to read.

Glossary section is good so far, but needs more words to be added.

The references section is excellent.

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Olfaction review:

Upon first glance of the page you immediately get the impression excellent presentation and a surplus of information. Most topics are well described although the history of discoveries layout is questionable and a table would present at a higher quality.
It is clear that the group has a high level of understanding through large amount of research; this is then transformed into chunks of knowledge in which are easily digestible for the reader. The page lacks visual encourage, I believe more detail into this would only benefit the page. The glossary could quite easily be expanded many terms throughout the text are absent from this list.
This page is almost parallel with embryological teaching aims. Citation & referencing is excellent. The way to improve this page would be reducing the weight of the text using innovative ideas to the present information in a more exciting way along side inclusion of more visual stimulus.
--[[User:Z3330795|Z3330795]] 09:53, 26 September 2012 (EST)

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Olfactory

The introduction, though brief, captured my attention and made me want to read more. It did exactly what is was supposed to do; provide an introduction to the topic, while keeping it interesting.
Both the history and the development timeline sections are well researched and referenced. For the timeline part, there are large chunks of text describing processes but with no images to support them. This makes it confusing and hard to follow (especially when describing the development process). The division of the abnormalities and the inclusion of the pathophysiology is very thorough and is done very well. This part was very interesting to read. Current research is also well structured, and more importantly, relates to the abnormalities describe above. Overall this group has done an exceptional job.

== External Links ==

Hey team... make sure you check the links i added to the external link section. They are great resources to use in your sections.

[[User:Z3333427|Z3333427]] 10:19, 21 August 2012 (EST)

== Group Topic Selection ==

So we have a choice between:

stem cells

Neuronal development

Sensory development

I personally don't have a particular preference but I think neural or sensory would be something different to touch on since there's still so much progressing research in the field.

'''Hey all :-). Thanks for getting the ball rolling. I like the latter two options, in particular neuronal development - from there we can pick a certain aspect and explore not only normal development but perhaps research complications and genes/factors implicated when things go wrong.
p.s. It would be great if we could figure out a regular time to meet during the week outside the lab so we can properly discuss and share our research'''

Just a heads up- Mark preferred that we don't put our names up anywhere on the wikipage for privacy purposes!

'''sensory system'''
hello everyone, it seems like the options we had chosen for sensory were picked before we had a chance and therefore I have asked Dr Hill for us to do the "hearing" system. I don't mind changing if the group chooses to do so, however, I thought it would be a good idea to have a topic locked in. Please let me know if you want to do a different topic

--[[User:Z3333427|Z3333427]] 11:32, 14 August 2012 (EST)

=Designation of parts=

There must be an addition of current research and technologies in each area

Make sure this is not presented as an essay (balance text and writing with images, tables etc)

Possibly a history of the development of understanding

[[User:Z3331264|Z3331264]] 11:54, 15 August 2012 (EST) Timeline and processes of development

--[[User:Z3374215|Z3374215]] 11:59, 15 August 2012 (EST)I would like to do a history section and the introduction

Please identify which part you want to be responsible for, keep in mind that you can work at any topic you would like.

Introduction: Andrew

History: Libby

Abnormalities: Stephanie

Future research: Libby (future research on normal function) Stephanie (future research on abnormalities/treatments)

Timeline: [[User:Z3331264|Z3331264]] 20:18, 22 August 2012 (EST)

==Progress of individual tasks and project queries==

[[User:Z3331264|Z3331264]] 20:18, 22 August 2012 (EST): I will be creating a table to indicate the timeline of development of olfaction during embryonic development. I will make changes to the initial table as I go along so as to avoid not contributing any online material until the end.

--[[User:Z3333427|Z3333427]] 00:58, 25 August 2012 (EST)The table is a really good idea, we should probably have at least another one as information becomes much more organised. Just to let you know that I changed it to Carnegie stages as most sources organise their information based on those stages, and keep in mind that the placodes dont form until week 11 or 12, so there is no need to have stages 1-10.

--[[User:Z3374215|Z3374215]] 17:52, 27 August 2012 (EST) I've got some information on historical developments but information is really difficult to find. I've made some progress but not sure how much more there is that I can do. In light of that I might also take a look at the subheading "Structure". It's referring to the physical structure of the developing olfactory system?

--[[User:Z3331264|Z3331264]] 19:33, 27 August 2012 (EST) Carnegie stages are a good idea! I also think its important to include a brief description of the development of the anatomy of the nose (turbinates etc) as well as a bit about the brain development in the locations of the olfactory nerve. Don't freak out when you read my additions, I do my research gradually, which means I will first add what I found in the textbook and then later on fill in the gaps plus add a research dimension with current lit.

--[[User:Z3333038|Z3333038]] 10:09, 29 August 2012 (EST) Hi all, you heard it from Mark today but just restating, even when doing draft work you must reference properly as you go along or you will be penalised.

--[[User:Z3331264|Z3331264]] 11:22, 29 August 2012 (EST) Decided to just stick to weeks rather than carnegie stages because sometimes between carnegies stages, little events occur which will make the table larger and more confusing!

--[[User:Z3333038|Z3333038]] 18:01, 29 August 2012 (EST) Hey Libby, I found a review article which contains a brief history on olfaction abnormalities in development in the introduction: http://www.springerlink.com.wwwproxy0.library.unsw.edu.au/content/288u546105v08575/fulltext.pdf

--[[User:Z3333038|Z3333038]] 19:26, 29 August 2012 (EST) Hi all, just letting you know im working through pathophysiology for Kallmann's syndrome on a word document at the moment and will post some as I go online to document progress. Currently working on a diagram demonstrating the abnormalities in the olfactory bulb neuronal connections.

--[[User:Z3333038|Z3333038]] 21:18, 30 August 2012 (EST) Completed my diagram and have uploaded it with referencing. I based my diagram on an image from a review article which I have referenced - have emailed Dr. Hill to check that all is alright in terms of copyright.

--[[User:Z3331264|Z3331264]] 22:25, 4 September 2012 (EST) : Hey everyone, this is the html code to add to your parts whenever you wish to place a link of a word to the glossary:

[[#Glossary |'''put the word you want linked to glossary here''']]

--[[User:Z3374215|Z3374215]] 17:18, 5 September 2012 (EST) Hi Stephanie, I found an interesting article about abnormal development of the olfaction bulb of mice when exposed to alcohol. Don't know if you'd seen it. http://www.ncbi.nlm.nih.gov/pubmed/21736737

I also read that article! Pretty interesting stuff

[[User:Z3333427|Z3333427]] 17:48, 7 September 2012 (EST) That is a good idea, please email Dr. Hill if you are unsure about anything as huge penalties apply for ignoring copyright. By the way our group project is looking good, more diagrams and tables similar to the one we have now would be great.

--[[User:Z3333038|Z3333038]] 08:21, 11 September 2012 (EST) Thanks for the article :-). I will add it to a section on congenital anosmia. I emailed him and he said it was absolutely fine, as long as I referenced my source information.

--[[User:Z3374215|Z3374215]] 12:00, 12 September 2012 (EST) Just a note to myself more than anything. I need to reference Julius Kollmann's textbook in the history section and add a diagram.

--[[User:Z3333038|Z3333038]] 20:12, 14 September 2012 (EST) Loving the page team! The drawings are great! Nearly finished my bit, just have to add a brief paragraph for the other congenital abnormalities and one more research article.

--[[User:Z3333038|Z3333038]] 22:35, 14 September 2012 (EST)Hey Libby I found this website for timeline/history: http://www.medlink.com/medlinkcontent.asp...it talks about discoveries of congenital olfactory defects.
--[[User:Z3333038|Z3333038]] 09:15, 15 September 2012 (EST)Completed abnormalities and submitted 3 current research articles. Happy to take on extra parts.

--[[User:Z3374215|Z3374215]] 12:06, 15 September 2012 (EST) Thanks Stephanie that site looks great! I'll check it out soon.

--[[User:Z3333038|Z3333038]] 11:06, 19 September 2012 (EST) Important! Hey guys, we really need to work on the development of each structure and the genes involved. Who can help me out?

--[[User:Z3333038|Z3333038]] 11:47, 19 September 2012 (EST)Note to self: Make section on external links.

--[[User:Z3331264|Z3331264]] 17:49, 20 September 2012 (EST) The table that I included walks through the timeline of development. I have slowly been adding more and more research including genes involved in patterning. But at the same time, I don't want to dive into too much information in order to maintain the balance between text and images. I have figured out a way to do this without making it all seem too simple, so just bear with me for the next week and you'll see it tie in well. Cheers

--[[User:Z3333038|Z3333038]] 09:52, 25 September 2012 (EST) I have stumbled across an extra abnormality - although it is more a structural defect rather than a sensory defect, it still relates to olfaction so I have added it in. Will keep it brief though as whilst it is a common nasal abnormality, it is not so much a sensory one. Also, Z3374215 and I are concerned - are you two alright with your parts? We know, like the rest of us you have other assessments but it's been a long while since we've seen any major contribution - if you're stuck we are happy to give you a hand.

--[[User:Z3374215|Z3374215]] 19:07, 25 September 2012 (EST) Hi guys, don't want to impinge on anyone elses work but I think I have to change a couple of generic features on the page. If you don't mind I'll just stick the external links in the section down the bottom with the others. I also may have to move or make smaller the initial image of the olfactory system as I think it is stopping a table from formatting properly. If you are unhappy with any of those small changes I make please feel free to put them back or let me know and I will. Cheers.

--[[User:Z3333038|Z3333038]] 10:37, 26 September 2012 (EST) Thinking to move adult structure and function between history of discoveries and time line of development for flow.

--[[User:Z3333038|Z3333038]] 08:52, 29 September 2012 (EST) Adoring the site everyone! The picture is so adorable :) I am planning to complete my part by monday maximum.

--[[User:Z3333038|Z3333038]] 15:41, 1 October 2012 (EST) After looking at the feedback, I thought it would be better to reorganise the genes section in abnormalities into a table.

--[[User:Z3333038|Z3333038]] 09:54, 2 October 2012 (EST) The tables I put in for abnormalities are doing this weird thing where the colours are not showing up. Libby, I remember you had the same problem - how did you fix it?
--[[User:Z3333038|Z3333038]] 10:40, 2 October 2012 (EST) All my content has been completed and refined. Now going back to proofread. If anyone needs a hand with anything please let me know.

--[[User:Z3374215|Z3374215]] 09:02, 5 October 2012 (EST) Hi guys, the page looks great, thanks for all your hard work.

File:Olfaction signal transduction.JPG

2012-10-04T23:01:20Z

Z3374215:

Olfaction signal transduction

"Signal transduction in the OSN. (A) Representation of the receptors, enzymes, and ion channels—present in the olfactory cilia—that transduce activity of the odorant receptor (OR) into changes in membrane potential and gene expression. Binding of an odorant to its cognate OR results in the activation of heterotrimeric G protein (Gαolf plus Gβγ). Activated Gαolf in turn activates type III adenylyl cyclase (AC3), leading to the production of cyclic AMP (cAMP) from ATP. cAMP gates or opens the cyclic nucleotide-gated (CNG) ion channel, leading to the influx of Na+ and Ca2+, depolarizing the cell. This initial depolarization is amplified through the activation of a Ca2+-dependent Cl− channel. In addition, cAMP activates protein kinase A (PKA), which can regulate other intracellular events, including transcription of cAMP-regulated genes. (B) Events in the nucleus of OSNs important for establishing and maintaining sensory neuron identity. Selection of a particular OR gene by the cell is thought to occur via interaction of a cis-regulatory locus control region with the proximal promoter of a single OR gene within a cluster of OR genes. This choice is stabilized—and the expression from all other OR genes in the genome is silenced—by an OR-dependent feedback loop, which ensures the expression of a single OR per sensory neuron. The mechanism underlying OR-mediated, OR gene silencing is at present not understood. OR-mediated activity also leads to transcriptional regulation of cAMP response element binding protein (CREB)–dependent gene expression via CREB's phosphorylation by PKA".

<pubmed>21041441</pubmed>

Published November 1, 2010 // JCB vol. 191 no. 3 443-452
The Rockefeller University Press, doi: 10.1083/jcb.201008163
© 2010 DeMaria and Ngai

This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

{{Template:Student Image}}

File:Vomeronasal Organ position.jpg

2012-10-03T02:32:56Z

Z3374215:

Student drawn image

This image demonstrates the position of the vomeronasal organ in relation to the olfactory bulb and tract. It was compiled from several web sources.

The vomeronasal organ is the organ of pheromone detection. Detection leads to behavioural and endocrinological changes<ref name="PMID22399397"><pubmed>22399397</pubmed></ref>. The human vomeronasal organ is a rudimentary structure and its function is still being actively debated, it is perhaps thought to have only a minor role in chemical communication between humans<ref name="PMID11369678"><pubmed>11369678</pubmed></ref>. The vomeronasal organ plays a much larger role in other animals such as amphibia, reptiles and nonprimate mammals<ref name=The Vomeronasal Organ>Eric B. Keverne. Science 22 October 1999: Vol. 286 no. 5440 pp. 716-720. The Vomeronasal Organ.</ref>

--[[User:Z8600021|Mark Hill]] 00:41, 3 October 2012 (EST) More supporting information could be supplied here. What is this image based upon?

{{Template:Student Image}}

'''References'''
<references/>

File:Vomeronasal Organ position.jpg

2012-10-03T02:32:05Z

Z3374215:

User:Z3374215

2012-10-03T00:04:39Z

Z3374215: /* Lab Attendance */

==Lab Attendance==

Lab 1 --[[User:Z3374215|Z3374215]] 11:49, 25 July 2012 (EST)

Lab 2 --[[User:Z3374215|Z3374215]] 10:06, 1 August 2012 (EST)

Lab 3 --[[User:Z3374215|Z3374215]] 10:06, 8 August 2012 (EST)

Lab 4 --[[User:Z3374215|Z3374215]] 12:01, 15 August 2012 (EST)

Lab 5 --[[User:Z3374215|Z3374215]] 10:05, 22 August 2012 (EST)

Lab 6 --[[User:Z3374215|Z3374215]] 10:08, 29 August 2012 (EST)

Lab 7 --[[User:Z3374215|Z3374215]] 10:14, 12 September 2012 (EST)

Lab 8 --[[User:Z3374215|Z3374215]] 11:34, 19 September 2012 (EST)

Lab 9 --[[User:Z3374215|Z3374215]] 10:10, 26 September 2012 (EST)

Lab 10 --[[User:Z3374215|Z3374215]] 10:04, 3 October 2012 (EST)

==Lab 1 Assessment==
'''1) Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.'''

The Nobel Prize for physiology or medicine in 2010 was awarded to Robert G. Edwards for his efforts in the development of In Vitro fertilization. Robert G. Edwards developed the idea of In Vitro fertilization since the 1950s. He first made fundamental discoveries in the life cycles of human eggs and the optimal time for fertilization before pairing with a gynecologist, Patrick Steptoe, and eventually seeing to the successful birth of an IVF baby in 1978. <ref>http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html</ref>.

'''2) Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).
'''
"The relative contributions of propulsive forces and receptor-ligand binding forces during early contact between spermatozoa and zona pellucida of oocyte" was published by the Journal of Theoretical Biology in Nov. 2011 <ref name= 'PMID22100500"><pubmed>22100500</pubmed></ref>. This report discusses the two main ways in which spermatozoa penetrate the zona pellucida of oocytes. The sperm utilize propulsive forces to assist in penetration. This is achieved through the motion of the flagella. The other factor important to penetration is the binding of sperm to ligands on the surface of the zona pellucida of the oocyte (ZP3). The report addresses the question of which of the cofactors is most imperative to the successful fertilization of the oocyte. A biomechanical model of the sperm-oocyte process was developed. It predicted that during early penetration the propulsive forces were stronger than the biochemical ligand binding. It was also predicted that the constant movement and overpowering force of the propulsion of sperm would make binding to ZP3 ligands difficult, making the large number of ZP3 receptors on the head of the sperm significantly important at this early stage.

===References===
<references/>

==Lab 2 Assessment==
'''1) Upload an image from a journal source relating to fertilization or the first 2 weeks of development as demonstrated in the practical class. Including in the image “Summary” window: An image name as a section heading, Any further description of what the image shows, A subsection labeled “Reference” and under this the original image source, appropriate reference and all copyright information and finally a template indicating that this is a student image.'''

'''Image:''' Expression of Endometrial CD98 in implantation<ref name:"PMID20976164"><pubmed>20976164</pubmed></ref>
[[Image:Expression of Endometrial CD98 in implantation.png|thumb|center|alt=Alt|Expression of Endometrial CD98 in implantation]]

'''2) Identify a protein associated with the implantation process, including a brief description of the protein's role (1-2 paragraphs).'''

A study has identified trophinin as a protein important to the adhesion implantation process. It is believed to be a single intrinsic protein that spans the membrane due to hydrophobic tendencies. This molecule can adhere without the aid of calcium unlike many cell adhesion molecules. Trophinin molecules bind with other trophinin molecule in trans structure on the cell surface. Immunostaining showed that antigens specific to the trophinin molecule can be found in both trophoblast cells and in the maternal epithelium near implantation sites of the embryo. The protein has been found to be encoded in the short arm of the X chromosome. It is also present in the mouse, sheep and bovine, along with monotremes and marsupials. It appears that the binding of the trophectoderm (consists of trophoblasts and is the connection between the blastocyst and the maternal cells) is essential to invasion and proliferation of cells. In embryonic cells trophinin induces and promotes invasion and proliferation. In maternal cells the same protein promotes apoptosis (controlled cell death) so as to allow the acceptance of the embryo. Therefore it is a dual signalling molecule. <ref name="PMID22717627"><pubmed>22717627</pubmed></ref>

===Reference===
<references/>

==Lab 3 Assessment==

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

The gestational age refers to the time since the last normal menstruation period<ref>Moore, K.L., 2011 ''The Developing Human'' 9th ed. W.B. Saunders</ref>. Whereas post-fertilisation age is calculated from the time of fertilization. There can be confusion between the terms espcially as gestational age is two weeks longer than post-fertilisation age<ref name:"PMID"15520122"><pubmed>15520122,</pubmed></ref>. Although in itself the term gestation age is confusing as there is no actual conceptus in until fertilisation but it is accepted by clinicians through widespread use<ref name:"PMID16006453"><pubmed>16006453</pubmed></ref>. As exact post-fetilisation age would be difficult to determine gestational age is used clinically. In assisted reproduction cases post-fertilisation age can be accurately determined but 2 weeks are generally added to age for ease of understanding<ref name:"PMID"15520122"><pubmed>15520122,</pubmed></ref>.

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

Somites form the dermis of the dorsal epithelium, skeletal muscles and some connective tissue, specifically, the vertebrae and ribs.<ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Paraxial Mesoderm: The Somites and Their Derivatives. Available from: http://www.ncbi.nlm.nih.gov/books/NBK10085/</ref>

===References===
<references/>

==Lab 4 Assessment==
'''1) Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.'''
Prenatal placental biopsy an invasive diagnostic technique for genetic abnormalities (such as trisomy 21) in the fetus. A karyotype is constructed allowing analysis of the chromosomes. It is used in the second and third trimester of pregnancy to confirm suspected malformations. Placental biopsies are sonographically guided<ref name:"PMID2712602"><pubmed>2712602</pubmed></ref>.
Chorionic villus testing is another invasive technique carried out transcervically in the first trimester to detect inherited disorders such as haemophilia <ref name:"PMID22250892"><pubmed>22250892</pubmed></ref>

'''2) Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''
Mesenchymal stem cells derived from the human umbilical cord have been used as a therapeutic treatment for neuromyelitis optica. Neuromyelitis optica is an autoimmune inflammatory disease that effects the optic nerve and spinal cord. Stem cells have been seen to provide differentiation potential to neural cells, secrete necessary factors and help regulate immunological function.
Five patients were treated with stem cell injections and then monitored for 18 months to analyse the effects both adverse and any improvements. Four out of the five patients gained some relief following treatment. Signs and symptoms decreased and the frequency of relapse was lessened. The neurological lesions also decreased in volume and severity as seen by MRI. The paper summarised that human umbilical cord stem cells were an appropriate therapy technique<ref name:"PMID22873728"><pubmed>22873728</pubmed></ref>.

===References===
<references/>

==Lab 7 Assessment==
'''1. (a) Provide a one sentence definition of a muscle satellite cell'''

Muscle satellite cells are progenitor cells and are involved in muscle growth and repair as they can induce regenerated muscle and additional satellite cells<ref name:”PMID12757751”><pubmed>12757751</pubmed></ref>

'''(b) In one paragraph, briefly discuss two examples of when satellite cells are activated.'''

A study investigating exercised induced satellite cell activation in skeletal muscle of growing and mature rats concluded that satellite cells are activated by acute sessions of prolonged eccentric exercise. It also concluded that exercise affected the proliferation of young mitotically active satellite cells<ref name:”PMID3693217”><pubmed>3693217</pubmed></ref>. Satellite cells are also activated when damage occurs. A study indicated that two variants of the IGF-I gene are necessary for activation of satellite cells. The study examined induced lesions to the anterior tibialis muscle of rats. The results showed that one variant of the gene which gives rise to a growth factor, MGF, is initially produced after injury and it activates satellite cells then IGF-IEa is expressed to maintain the repair process <ref>M Hill1, A Wernig, G Goldspink '''Muscle satellite (stem) cell activation during local tissue injury and repair''' Journal of Anatomy:2003, 203(1);89-99</ref>

'''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.'''

In a study involving 12 human patients suffering from spinal cord injuries a section of the vastus lateralis muscle was biopsied at 3 intervals within the first 6month following injury. From 6-24 weeks after injury they showed 27-56% atrophy of Type I, IIa and IIax+IIx fibers. There was increased conversion between muscle types, type IIa decreased and type IIax+IIx increased. However there was little change in proportion of tpye I fibers during this period<ref name:"PMID9887150"><pubmed>9887150</pubmed></ref>

===Reference===
<references/>

==Lab 8 Assessment - Peer Review==
===Vision===
The layout of the page is relatively good. If anything it appears little too image heavy at the moment. On the note of images, the referencing is good but don't forget to include the student template note with each image. The inclusion of some student drawn images in great to see but it might be an idea to make the labels larger as they are hard to read. The use of subheadings is great, a really logically well set out page. The references need a bit of work, some are spread sporadically throughout the page and some in the references section just list the URL along with the error on reference number 13.

The introductory is brief but alright. However the first two images are largely similar, not sure why both need to be included. Perhaps if possible it would be nice to link each of the main anatomical bullet points you have listed in your introduction to their associated developmental paragraph further down the page.

The History of development is coming along nicely but perhaps would be easier to read if it was in the format of a table. Also the Atlas of the Development of Man needs to be properly referenced with the author in the reference section. It would be nice to have some information relating to the pictures uploaded in this section.

The section on Development is well done and it is interesting to look at the individual development of each structure. It might be an idea to include some more references to when each structural development occurs. Current Research really needs some more content. The glossary is a nice addition and helpful.

===Somatosensory===
This page has made good use of subheadings ensuring that the main topics are easily accessible from the contents box. The project appears a little text heavy, it may help to include some other images. Also don't forget to add the student template note on the student drawn image. The reference list at the end is not particularly extensive. Perhaps this can be worked on by collecting the loose references in the text and adding them to the final reference section. Overall some sections of the page seem to have little to with embryology and more focused on adult function.

The introduction, while good, seems to lack any original voice, rather seeming to consist almost entirely of research done by others. The referencing in this section is also confusing with (Lagercrantz, Hanson, Evrard & Rodeck, 2001) being listed before any text. Referencing in this format also makes the page seem like a report or essay rather than a web page. There is also mention of a picture that does not exist. The historic section is brief and rather hard to digest as it is just a chunk of text. Perhaps putting this information into a table and developing it a little would help here.

The section on Central Somatosensory Differentiation was particularly well done. The inclusion of the student drawn image making all the difference. The general structure of this section is also commendable.

The subtitles "Touch", "Pain", "Heat/Cold" and "Pressure" are somewhat abrupt and don't particularly indicate what the section is discussing. This section in particular could do with the addition of some images. The information under Touch could perhaps be a little more heavily researched but is generally well written. Breaking the Pain section into some smaller paragraphs could be useful. The Hot/Cold and Pressure sections are well done excepting the random references to some articles.

Current research section could do with some more information. There are several words throughout the content that could do with being linked to an explanation in the glossary such as the "dorsal column-medial lemniscal system". The external links section is a good addition but it might be helpful to explain more clearly what each links to, especially the last three.

===Taste===
Initially the page seems to have a good balance between text and diagrams/photographs. However the figures included are not properly labelled once you click on the file and some of them don't appear to have any copyright information included. Some of the pictures could do with being a bit smaller as they take up a large proportion of the page. The student drawn image of the tongue is particularly impressive but does still need to have the student template included. The references seem limited in comparison to other groups perhaps suggesting a lack of depth or variety of research. There also appears to be a coding problem relating to reference number 5. The general layout and use of subheadings is great. It may be useful to link the words in the glossary to their occurrence in the text.

The introductory paragraphs are very well written. They are easy to understand and interesting and give a good overview of how taste functions. Similarly the section on taste map is well written clearly explaining the neurological factors associated with taste. However the presence of the picture in isolation is confusing as it is representing an the old method of taste association. Perhaps this would be resolved if a diagram of the newer taste map was also included. Also you say that the old taste map has been disproved by recent research but that research is not referenced. In fact it appears that very little of that section is referenced. The section on cortical areas is well done.

The timeline of developmental processes is good, the table an easy visual format and the information concise and effective. The only point of contention would be the direct quote in Wk8-9 which seems out of place in comparison to the remainder of the entries which are nicely paraphrased. The history section is similarly well done being extensive and comprehensive. That is excepting some Pub Med references which are just placed in the text rather than in the reference list at the bottom. While interesting and well written the part detailing the Adult Tongue and Taste Buds seems out of place in a embryology course.

The sections on the effect of gene expression on the formation of taste abnormalities and current research are good. However it may be useful to put the information regarding each picture as a caption rather than plain text.

It will be interesting to see what is put in the section "Image Gallery"

===Abnormal Vision===
Your introduction is relatively well written and the brief explanation of new terms such as microphthalmia was particularly useful. Perhaps it would be possible to break the text into two paragraphs to make reading easier.
It is really good to see a section included about normal eye development as it provides a basis of understanding for the remainder of the page. Concise and to the point and not too complex, it's great. Only suggestion would be to place it in a table perhaps with each Carnegie stage a new entry.

Layout of abnormalities is very logical covering the main areas of developmental abnormalities. However it is slightly confusing that immediately under the title Abnormal Lens Development more information on normal development is given. Allocating the defects to their associated individual genes is good but perhaps instead of a dotpoint a subheading would be of more use. The actual information is clearly and effectively written. The inclusion of the pictures clearly illustrates the abnormalities but their placement is a little odd. Perhaps they are too large. The captions on the pictures are appropriate and the pictures are appropriately referenced and it is great that the link to the picture contains more information.

Under the title "Ocular Manifestations" perhaps indicate what the two sections are, just so the following on sections make sense and don't appear disjointed. The sections on the genetic caused abnormalities is fascinating and very well written. The timeline included in the information about Leber Congenital Amaurosis is particularly interesting. The spacing in the section on genes associated with Anophthalmia and Microphthalmia appears slightly strange. The figures included are particularly illustrative and appropriate. Similarly the section on environmentally caused abnormalities is really well written and interesting.

Perhaps a more extensive section on current research could be included. If possible, link the words in the glossary to where they appeared in the text. This is the coding if you don't have it [[#Glossary|'''Words for Glossary''']]. Just add that in place of the word when you first mention it in the text. The citing and referencing is really well done. It also shows a great depth of research. The figures/photographs so far included are brilliant but the inclusion of a student drawn diagram somewhere if possible would be effective. Also try and fix the general layout of the project, possibly including some more subheadings. In general the content relates to the the course and is pitched at an appropriate level. Hope this helps.

===Hearing===
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.

==Lab 9==
'''1) Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

Hes1 is a target gene associated with notch signalling (a type of cell signaling pathway). It affects the proliferation and differentiation of progenitor cells. mic lacking the Hes 1 gene were observed to analyse the genes involvement in thyroid analyses. In a normal mouse the gene was expressed after E9.5. Hes1 lacking mice presented a smaller thyroid surface area at all stages and the fusion of the median anlage and ultimobranchial bodies was significantly delayed. It was suggested that the Hes1 gene is important for control of final number of thyrocyte and C-cell progenitors and ensuring adequate differentiation and endocrine function of these cells<ref name = "PMID21364918"><pubmed>21364918</pubmed></ref>.

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

Teeth form from the ectodermal layer of the oral cavity in association with the surrounding mesoderm. Specialised ectodermal cells termed ameloblasts secrete enamel. Mesenchymal mesoderm is responsible for other dental structures. Other specialised cells involved in tooth formation include odonoblasts and cementoblasts.<ref>John F. Neas, 2002 ''Human Anatomy Fourth Edition'', Chapter 4, Benjamin Cummings. Sourced from: http://cwx.prenhall.com/bookbind/pubbooks/martini10/chapter4/custom3/deluxe-content.html </ref>

===References===
<references/>

2012 Group Project 4

2012-10-02T23:52:42Z

Z3374215: /* History of Discovery */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
|[[File:Vomeronasal Organ position.jpg|thumb|right|200px|alt=Alt|''Vomeronasal Organ position''']]

Discovery of [[#Glossary|'''Vomeronasal organ''']] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|'''hypogonadism''']] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name="PMID15836430"><pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|'''epiblast''']], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of [[#Glossary|'''ectoderm''']]<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|'''cribriform plate''']]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia and midline anatomic defects) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for revealing the large number of genes involved in odour reception. <ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|350px|right|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]
[http://www.example.com Nasal Cavity]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells. <ref name="PMID7143026"><pubmed>7143026</pubmed></ref>.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.<ref name="PMID17468753 "><pubmed>17468753 </pubmed></ref>.

[http://www.ncbi.nlm.nih.gov/books/NBK10896/ Olfactory epithelium]
==== Olfactory Bulb ====

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined. The olfactory bulb is essential for olfaction as it transmits information from the olfactory epithelium and up to the brain. The bulb receives input from olfactory nerves which constitutes the axons of olfactory receptor neurons. <ref name="PMID12951145 "><pubmed>12951145</pubmed></ref>.

Structures known as glomeruli form by a number of olfactory axons joining together such that each glomerulus obtain information from olfactory neurons which have the identical odour receptors. These glomeruli structures are also surrounded by dendrites belonging to mitral cells which transmit electrical signals to the olfactory cortex in the brain.<ref name="PMID16269360"><pubmed>16269360</pubmed></ref>.

==== Cribiform plate ====

The cribiform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groove allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha. If the cribriform plate happens to get fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose. <ref name="PMID11226964"><pubmed>11226964</pubmed></ref>.

== Normal Function ==

===Olfactory Signal Transduction===

[[File:New olfactory bulb.jpg|450px|thumb|right|Olfactory Bulb]]

Olfactory Signal Transduction is initiated by any substance that emit molecules known as odours. The olfactory transduction is dependent upon the dissolving of these odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors in order for chemical signals to be converted into electrical signals. The transformation into electrical signal is essential for signal transduction for the brain to perceive the initial odourants as smell. <ref name="PMID18066954"><pubmed>18066954</pubmed></ref>.

When odorant molecules bind to receptors in olfactory epithelium, a G protein coupled receptors known as G(αolf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP (cAMP). In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions by binding to and opening cyclic nucleotide gated ion channel to travel through the membrane and enter the cell. <ref name="PMID19652915"><pubmed>19652915</pubmed></ref>. The main effect of ion entry into the cell is depolarisation, and activation of chloride channels resulting in greater depolarisation by the efflux of chloride ions. If the depolarization in the cell is great enough, an action potential is generated on the axon of the receptor cell and transferred to the brain through the olfactory bulb.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

Similar to other G-protein mediated pathways, the olfactory sensory neuron is exposed to negative feedback by the cAMP cascade activated by odours. The negative feedback loop has been discovered to be responsible for the adaption of odours and deactivation of response after exposure for a certain period of time. <ref name="PMID19804753"><pubmed>19804753</pubmed></ref>.

[http://www.youtube.com/watch?v=dIDBG-UPRUI&feature=related| Olfactory Signal Transduction]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
* All five facial swellings form initially surrounding the stomodeum.

* The [[#Glossary |'''frontonasal prominence''']] is the facial swelling which gives rise to [[#Glossary | '''olfactory placodes''']]. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>.

An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. Mesencephalic region produced neural crest cells which contributed to the frontonasal mass.<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>

* These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

* Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

* Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref name="PMID15454774"><pubmed>15454774</pubmed></ref>
||
[[File:week4.jpg|200px|thumb|right|Embryo at week 4]]
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

* As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

* The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit as the face folds, dividing the frontonasal prominence into the lateral and medial nasal processes.These pits deepen as the surrounding mesenchyme proliferates to form '''primordial nasal sacs''' which grow dorsally but remain ventral to the forebrain. <ref name="PMID15454774"><pubmed>15454774</pubmed></ref> These sacs are separated from the oral cavity via the '''oronasal membrane'''.

* '''Glial cells''': Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref>

||
[[File:Week5.jpg|200px|thumb|right|Embryo at week 5]]
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
* '''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

* The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and [[#Glossary |'''nasal septum''']].<ref name="PMID438867"><pubmed>438867</pubmed></ref>

* The oronasal membrane ruptures by the end of this week, allowing communication between the nasal and oral cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* '''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
The superior, middle, and inferior nasal conchae develop as the lateral walls of the nasal cavities proliferate and so elevate.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref name="PMID15454774"><pubmed>15454774</pubmed></ref>

* '''Vomeronasal Organ Primordium''': Visible as epithelial swellings on the lower medial aspect of the nasal pit.<ref name="PMID9712194"><pubmed>9712194</pubmed></ref>. The anterior part can be seen as an indentation and the posterior part can be seen as continuous epithelium with the nasal septum. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* [[#Glossary |'''Vomeronasal Organ''']]: The VNP's are no longer visible but are instead in the form of bilateral tubes with well delineated lumens, that open anteriorly into the nasal cavity.<ref name="PMID11117628"><pubmed>11117628</pubmed></ref> The VNO epithelium is thicker than respiratory epithelium up until 12 weeks when the respiratory epithelium overtakes in thickness<ref name="PMID11117628"><pubmed>11117628</pubmed></ref>. The medial sides of the VNO's proliferate into thicker, microvillous sensory epithelium while the the lateral sides are thinner, receptor-free, ciliated epithelium. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

||
[[File:Week6.jpg|200px|thumb|right|Embryo at week 6]]
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
* '''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla.
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* '''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse to form the primary palate.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, [[#Glossary |'''Nasal fin.''']]<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* '''Secondary Palate''': Formed as the two palatine shelves extend medially and fuse at the midline at the primary palate.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The lining of the olfactory placode differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

- '''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

- '''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

- '''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

* At the end of the 7th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated [[#Glossary |'''cribriform plate''']]. <ref name="PMID15454774"><pubmed>15454774</pubmed></ref>

* [[#Glossary |'''Olfactory bulb''']] growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* [[#Glossary |'''Olfactory nerve''']] formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.<ref name="PMID11117628"><pubmed>11117628</pubmed></ref>
As a result, the CNS olfactory tracts look stalk-like.

* '''Olfactory nerve''': the '''olfactory tract''' and bulb together.

* By this stage the olfactory nerve is divided into a medial and lateral plexus. The medial plexus receives the VNO axon strands which are directed towards the caudal part of the olfactory bulb. Meanwhile the lateral plexus receives axon elongation from the olfactory epithelium and is directed towards the lateral edge of the olfactory bulb. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* Migration of Gonadotropin Releasing hormone along the vomeronasal nerve between weeks 6 to 8- plays a part in hypothalamus development.<ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
[[File:Week7.jpg|200px|thumb|right|Embryo at week 7]]
|- bgcolor="#BCD4E6"
|''Week 8/Fetal development''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
* '''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* '''VNO:''' At this stage, the number of ciliated VNO epithelial cells increases into the late fetal period whilst the number of receptor cells decreases. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>
The degeneration of the VNO is noted by the closure of the duct and formation of a cyst like structure in the nasal septum. However, in most adults, the duct is left opened to a certain degree.<ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
||
[[#Normal Function |'''See normally developed sensory structures of olfaction''']]

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann Syndrome|'''Kallmann Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

------

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by narrowing or complete obliteration of the nasal aperture by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. The following models have been proposed to explain how choanal atresia may occur in the developing human.

<table>
{| width=100%
|-bgcolor="#FF9900 "
| width=20%|'''Risk Factor Model'''
| width=80%|'''Description'''
|-bgcolor="#FFFF99"
| ''' Embryonic'''
| Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence":
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter<ref name="PMID19328897"/>
* Abnormal persistence of mesoderm, resulting in adhesions in the nasochoanal region<ref name="PMID19328897"/>
* Misdirection of neural crest cell migration <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>
|-bgcolor="#FFCC66"
| '''Genetic'''
|
* A study <ref name="PMID3679682"><pubmed> 3679682</pubmed></ref> reported that 30% of children with choanal atresia had '''CHARGE Syndrome''' which stands for: Coloboma, Heart defect, Atresia Choanae, Retarded Growth and development, Genital hypoplasia, Ear anomalies or deafness <ref name="PMID19328897"/>.
* CHD7 gene on chromosome 8q12.1 found in 64% of CHARGE syndrome patients though its function is unknown. <ref name="PMID16155193"><pubmed>16155193</pubmed></ref>
|-bgcolor="#FFFF99"
| '''Molecular'''
|
* '''Thionamides and Hyperthyroidism''': A number of studies reported an increased incidence of choanal atresia in babies of hyperthyroid mothers treated with thionamides<ref name="PMID3688031"><pubmed>3688031</pubmed></ref><ref name="PMID9450891"><pubmed>9450891</pubmed></ref><ref name="PMID18698631"><pubmed>18698631</pubmed></ref>. The majority of hyperthyroid mothers had elevated levels of stimulating antibody for the thyrotropin receptor<ref name="PMID19328897"/>. Human studies and animal models have shown that elevated thyrotropin alters the expression of the growth factor FGF, FGF receptors and angiogenic factors which may play a role in development of choanal atresia<ref name="PMID12746216"><pubmed>18698631</pubmed></ref><ref name="PMID11397875"><pubmed>11397875</pubmed></ref>. However, further research is required in order to determine the exact mechanisms involved.

* '''Retinoic Acid''': Retinoic acid is the product of vitamin A metabolism by retinaldehyde dehydrogenase (Raldh)<ref name="PMID19328897"/>. Mouse models showed that an absence of Raldh causes choanal atresia, resulting in respiratory distress and death of Raldh3 knockout mutants at birth<ref name="PMID14623956"><pubmed>14623956</pubmed></ref>.
|}
</table>

====Clinical Features====

[[File:Choanal atresia computed tomography 01.jpg|300px|thumb|right|Computed Tomography of Choanal Atresia]] Neonates are obligate nose breathers, hence neonatal nasal obstruction as seen in choanal atresia is a serious deformity. In order to avoid severe hypoxia and death, immediate diagnosis and intervention are key<ref name="PMID11232465"><pubmed>11232465<pubmed/></ref>. The severity of the clinical features of choanal atresia depends on the whether the obstruction is unilateral or bilateral <ref name="PMID19328897"/>.

'''Bilateral'''
* At birth present with ''asphyxia neonatorum'': pathological changes caused by hypoxia from affected respiration. A medical emergency requiring an oral airway tube or intubation then immediate surgical intervention<ref name="PMID19328897"/><ref name="PMID12567078"><pubmed>12567078<pubmed/></ref>
* Obvious airway obstruction <ref name="PMID19328897"/>
* Stridor, a harsh vibrating sound when breathing <ref name="PMID19328897"/>
* Paradoxical cyanosis: cyanosis is present in the infant at rest but improves with exertion such as crying <ref name="PMID19328897"/>

'''Unilateral'''
* Not as life threatening as bilateral choanal atresia; more often diagnosed in childhood than in infancy <ref name="PMID19328897"/><ref name="PMID12567078"/>
* Mucoid rhinorrhea, constant mucous fluid discharge from nose <ref name="PMID19328897"/><ref name="PMID12567078"/>
* Dysosmia, distorted olfaction <ref name="PMID12567078"/>
* Obstructive sleep apnea <ref name="PMID12567078"/>

------

===Kallmann Syndrome===
====Introduction and Epidemiology====
[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|500px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]Kallmann syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb (OB) is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract. As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

'''Genetic Factors'''
In Kallmann syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations in six genes and the proteins they encode (see table below) have been attributed to Kallmann syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis of Kallmann Syndrome are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>. Note that CHD7 can also be mutated in Kallmann's syndrome patients, though these individuals tend to have additional features that are part of the CHARGE syndrome phenotype described in the section on [[#Choanal Atresia|'''Choanal Atresia''']]<ref name="PMID19021638"><pubmed>19021638</pubmed></ref>.

<table>
{| width=100%
|-bgcolor="#FF9900"
| width=9%|'''Gene'''
| width=20%|'''Mode of Inheritance'''
| width=50%|'''Role in Kallman’s Syndrome'''
|-bgcolor="#FFFF99"
| '''KAL1'''
| X-linked
| KAL1 normally encodes glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
|-bgcolor="#FFCC66"
| '''FGFR1 (KAL2)'''
| Autosomal-dominant <ref name="PMID20117945"/>
| FGFR1 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/> <ref name="PMID12627230"><pubmed>12627230</pubmed></ref>. When absent, Kallmann syndrome arises due to agenesis or digenesis of the olfactory bulb and failure of GnRH neuronal development and migration.
|-bgcolor="#FFFF99"
| '''FGF8'''
| Autosomal-dominant <ref name="PMID20117945"/>
| Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation. Absence produces similar phenotype to KAL2 mutation<ref name="PMID20117945"/>.
|-bgcolor="#FFCC66"
| '''PROKR2 (KAL3)'''
| Monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID20389090"><pubmed>20389090</pubmed></ref><ref name="PMID18826963"><pubmed>18826963</pubmed></ref>.
| Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"/>.. However, the exact role in Kallmann syndrome has yet to be clarified<ref name="PMID18826963"/>..
|-bgcolor="#FFFF99"
| '''PROK2 (KAL4)'''
| Hypothesised to have mendelian autosomal recessive transmission in addition to oligogenic transmission<ref name="PMID20389090"/>.
| Encodes the PROKR2 ligand<ref name="PMID18826963"/>. When PROK2 mutated, the ligand is not expressed preventing prokineticin receptor-2 activation; this produces similar effects to PROKR2 abnormalities.

|}
</table>

====Clinical Features====

Kallmann Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell<ref name="PMID22882983"/>. There exists additional characteristics that are not specific to Kallmann syndrome but may aid in correct diagnosis of this particular HH<ref name="PMID22882983"/>. The following characteristics of Kallmann syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* Cryptorchidism: Failure of one or both testes to migrate into the scrotum during male foetus development.
* Gynaecomastia: The development of abnormal mammary glands in males characterised by enlarged breasts.
* Amennorhoea: the absence of menstruation, in females

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification
* Unilateral renal [[#Glossary |'''aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* Pes cavus: Also called clawfoot, refers to a deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. <ref name="PMID16932275"/>
* Neurological symptoms
** Synkinesia: Patients can conduct voluntary movements, however, with accompanied involuntary muscular movements.
** Abnormalities in eye movement
** Cerebellar ataxia: Reduced control over muscle coordination arising from defects or damage to the cerebellum.
** Evoked horizontal nystagmus: fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.
** Sensorineural deafness
** Spatial attentional abnormalities
** Spastic paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>

===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmanb syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
[http://www.ncbi.nlm.nih.gov/pubmed/21543621 Forni PE et al.]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]][http://www.ncbi.nlm.nih.gov/pubmed/21943152 ''The dual origin of the peripheral olfactory system''] also investigated the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
[http://www.ncbi.nlm.nih.gov/pubmed/22906231 Shaker T. et al.] published a paper in August this year looking into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular section of the research looked to determine whether Neurog1 and Neurog2 were required for olfactory bulb development. A loss-of-function technique was utilised to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
[[File:Absence_of_CSFR1_Impacts_Normal_Development_of_Brain_Architecture.jpg|200px|thumb|left|'''Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development'''- Absence of CSF-1R results in perturbed brain architecture.]]A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cribiform Plate''': The inferior surface of the ethmoid bone which roofs the nasal cavities.

'''Ectoderm:''' The outermost layer of the trilaminar embryo. Differentiates to form structures including the epidermis and neural tissue.

'''Epiblast:''' The collective term for embryonic mesoderm and ectoderm before differentiation

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Frontonasal Prominence''': An ectodermal expansive process that arises during the third week of embryonic development and forms the forehead and nasal bridge.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nasal Fin''': A plate-like ectodermal structure that forms between the medial and lateral prominences that thins to the form the oronasal membrane.

'''Nasal Septum''': Separates the left and right airways of the nose into nostrils. It is made up of the perpendicular plate of ethmoid bone, the vomer bone, cartilage and the crest of the maxillary and palatine bones.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Olfactory Placode''': A thickened area of ectoderm on the frontonasal prominence which contributes to the development of the olfactory sensory system.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones. A rudimentary organ in humans.

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

[http://kallmanns.org/ The Kallmann's Syndrome Organisation]

==Gallery==
<gallery>
Image:Vomeronasal_Organ_position.jpg
Image:Nasal_placode_diagram.jpeg
Image:Olfactory_bulb_and_epithelium.png
Image:Olfactory_epithelium.jpg
Image:New_olfactory_bulb.jpg
Image:Choanal_atresia_computed_tomography_01.jpg
Image:Normal_Neuronal_Migration_into_the_Olfactory_Bulb_Compared_to_Kallmann's_Syndrome.jpg
Image:Neural_crest-derived_cells_in_the_embryonic_olfactory_epithelium.jpg
Image:Absence_of_CSFR1_Impacts_Normal_Development_of_Brain_Architecture.jpg
Image:week4.jpg
Image:week5.jpg
Image:week6.jpg
Image:week7.jpg
</gallery>

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-10-02T23:45:06Z

Z3374215: /* Glossary */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
|[[File:Vomeronasal Organ position.jpg|thumb|right|200px|alt=Alt|''Vomeronasal Organ position''']]

Discovery of [[#Glossary|'''Vomeronasal organ''']] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|'''hypogonadism''']] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|'''epiblast''']], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of [[#Glossary|'''ectoderm''']]<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|'''cribriform plate''']]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia and midline anatomic defects) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for revealing the large number of genes involved in odour reception. <ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|350px|right|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]
[http://www.example.com Nasal Cavity]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells. <ref name="PMID7143026"><pubmed>7143026</pubmed></ref>.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.<ref name="PMID17468753 "><pubmed>17468753 </pubmed></ref>.

[http://www.ncbi.nlm.nih.gov/books/NBK10896/ Olfactory epithelium]
==== Olfactory Bulb ====

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined. The olfactory bulb is essential for olfaction as it transmits information from the olfactory epithelium and up to the brain. The bulb receives input from olfactory nerves which constitutes the axons of olfactory receptor neurons. <ref name="PMID12951145 "><pubmed>12951145</pubmed></ref>.

Structures known as glomeruli form by a number of olfactory axons joining together such that each glomerulus obtain information from olfactory neurons which have the identical odour receptors. These glomeruli structures are also surrounded by dendrites belonging to mitral cells which transmit electrical signals to the olfactory cortex in the brain.<ref name="PMID16269360"><pubmed>16269360</pubmed></ref>.

==== Cribiform plate ====

The cribiform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groove allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha. If the cribriform plate happens to get fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose. <ref name="PMID11226964"><pubmed>11226964</pubmed></ref>.

== Normal Function ==

===Olfactory Signal Transduction===

[[File:New olfactory bulb.jpg|450px|thumb|right|Olfactory Bulb]]

Olfactory Signal Transduction is initiated by any substance that emit molecules known as odours. The olfactory transduction is dependent upon the dissolving of these odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors in order for chemical signals to be converted into electrical signals. The transformation into electrical signal is essential for signal transduction for the brain to perceive the initial odourants as smell. <ref name="PMID18066954"><pubmed>18066954</pubmed></ref>.

When odorant molecules bind to receptors in olfactory epithelium, a G protein coupled receptors known as G(αolf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP (cAMP). In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions by binding to and opening cyclic nucleotide gated ion channel to travel through the membrane and enter the cell. <ref name="PMID19652915"><pubmed>19652915</pubmed></ref>. The main effect of ion entry into the cell is depolarisation, and activation of chloride channels resulting in greater depolarisation by the efflux of chloride ions. If the depolarization in the cell is great enough, an action potential is generated on the axon of the receptor cell and transferred to the brain through the olfactory bulb.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

Similar to other G-protein mediated pathways, the olfactory sensory neuron is exposed to negative feedback by the cAMP cascade activated by odours. The negative feedback loop has been discovered to be responsible for the adaption of odours and deactivation of response after exposure for a certain period of time. <ref name="PMID19804753"><pubmed>19804753</pubmed></ref>.

[http://www.youtube.com/watch?v=dIDBG-UPRUI&feature=related| Olfactory Signal Transduction]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
* All five facial swellings form initially surrounding the stomodeum.

* The [[#Glossary |'''frontonasal prominence''']] is the facial swelling which gives rise to [[#Glossary | '''olfactory placodes''']]. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>.

An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. Mesencephalic region produced neural crest cells which contributed to the frontonasal mass.<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>

* These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

* Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

* Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref name="PMID15454774"><pubmed>15454774</pubmed></ref>
||
[[File:week4.jpg|200px|thumb|right|Embryo at week 4]]
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

* As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

* The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit as the face folds, dividing the frontonasal prominence into the lateral and medial nasal processes.These pits deepen as the surrounding mesenchyme proliferates to form '''primordial nasal sacs''' which grow dorsally but remain ventral to the forebrain. <ref name="PMID15454774"><pubmed>15454774</pubmed></ref> These sacs are separated from the oral cavity via the '''oronasal membrane'''.

* '''Glial cells''': Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref>

||
[[File:Week5.jpg|200px|thumb|right|Embryo at week 5]]
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
* '''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

* The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and [[#Glossary |'''nasal septum''']].<ref name="PMID438867"><pubmed>438867</pubmed></ref>

* The oronasal membrane ruptures by the end of this week, allowing communication between the nasal and oral cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* '''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
The superior, middle, and inferior nasal conchae develop as the lateral walls of the nasal cavities proliferate and so elevate.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref name="PMID15454774"><pubmed>15454774</pubmed></ref>

* '''Vomeronasal Organ Primordium''': Visible as epithelial swellings on the lower medial aspect of the nasal pit.<ref name="PMID9712194"><pubmed>9712194</pubmed></ref>. The anterior part can be seen as an indentation and the posterior part can be seen as continuous epithelium with the nasal septum. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* [[#Glossary |'''Vomeronasal Organ''']]: The VNP's are no longer visible but are instead in the form of bilateral tubes with well delineated lumens, that open anteriorly into the nasal cavity.<ref name="PMID11117628"><pubmed>11117628</pubmed></ref> The VNO epithelium is thicker than respiratory epithelium up until 12 weeks when the respiratory epithelium overtakes in thickness<ref name="PMID11117628"><pubmed>11117628</pubmed></ref>. The medial sides of the VNO's proliferate into thicker, microvillous sensory epithelium while the the lateral sides are thinner, receptor-free, ciliated epithelium. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

||
[[File:Week6.jpg|200px|thumb|right|Embryo at week 6]]
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
* '''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla.
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* '''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse to form the primary palate.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, [[#Glossary |'''Nasal fin.''']]<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* '''Secondary Palate''': Formed as the two palatine shelves extend medially and fuse at the midline at the primary palate.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The lining of the olfactory placode differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

- '''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

- '''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

- '''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

* At the end of the 7th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated [[#Glossary |'''cribriform plate''']]. <ref name="PMID15454774"><pubmed>15454774</pubmed></ref>

* [[#Glossary |'''Olfactory bulb''']] growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* [[#Glossary |'''Olfactory nerve''']] formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.<ref name="PMID11117628"><pubmed>11117628</pubmed></ref>
As a result, the CNS olfactory tracts look stalk-like.

* '''Olfactory nerve''': the '''olfactory tract''' and bulb together.

* By this stage the olfactory nerve is divided into a medial and lateral plexus. The medial plexus receives the VNO axon strands which are directed towards the caudal part of the olfactory bulb. Meanwhile the lateral plexus receives axon elongation from the olfactory epithelium and is directed towards the lateral edge of the olfactory bulb. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* Migration of Gonadotropin Releasing hormone along the vomeronasal nerve between weeks 6 to 8- plays a part in hypothalamus development.<ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
[[File:Week7.jpg|200px|thumb|right|Embryo at week 7]]
|- bgcolor="#BCD4E6"
|''Week 8/Fetal development''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
* '''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* '''VNO:''' At this stage, the number of ciliated VNO epithelial cells increases into the late fetal period whilst the number of receptor cells decreases. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>
The degeneration of the VNO is noted by the closure of the duct and formation of a cyst like structure in the nasal septum. However, in most adults, the duct is left opened to a certain degree.<ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
||
[[#Normal Function |'''See normally developed sensory structures of olfaction''']]

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann Syndrome|'''Kallmann Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

------

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by narrowing or complete obliteration of the nasal aperture by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. The following models have been proposed to explain how choanal atresia may occur in the developing human.

<table>
{| width=100%
|-bgcolor="#FF9900 "
| width=20%|'''Risk Factor Model'''
| width=80%|'''Description'''
|-bgcolor="#FFFF99"
| ''' Embryonic'''
| Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence":
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter<ref name="PMID19328897"/>
* Abnormal persistence of mesoderm, resulting in adhesions in the nasochoanal region<ref name="PMID19328897"/>
* Misdirection of neural crest cell migration <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>
|-bgcolor="#FFCC66"
| '''Genetic'''
|
* A study <ref name="PMID3679682"><pubmed> 3679682</pubmed></ref> reported that 30% of children with choanal atresia had '''CHARGE Syndrome''' which stands for: Coloboma, Heart defect, Atresia Choanae, Retarded Growth and development, Genital hypoplasia, Ear anomalies or deafness <ref name="PMID19328897"/>.
* CHD7 gene on chromosome 8q12.1 found in 64% of CHARGE syndrome patients though its function is unknown. <ref name="PMID16155193"><pubmed>16155193</pubmed></ref>
|-bgcolor="#FFFF99"
| '''Molecular'''
|
* '''Thionamides and Hyperthyroidism''': A number of studies reported an increased incidence of choanal atresia in babies of hyperthyroid mothers treated with thionamides<ref name="PMID3688031"><pubmed>3688031</pubmed></ref><ref name="PMID9450891"><pubmed>9450891</pubmed></ref><ref name="PMID18698631"><pubmed>18698631</pubmed></ref>. The majority of hyperthyroid mothers had elevated levels of stimulating antibody for the thyrotropin receptor<ref name="PMID19328897"/>. Human studies and animal models have shown that elevated thyrotropin alters the expression of the growth factor FGF, FGF receptors and angiogenic factors which may play a role in development of choanal atresia<ref name="PMID12746216"><pubmed>18698631</pubmed></ref><ref name="PMID11397875"><pubmed>11397875</pubmed></ref>. However, further research is required in order to determine the exact mechanisms involved.

* '''Retinoic Acid''': Retinoic acid is the product of vitamin A metabolism by retinaldehyde dehydrogenase (Raldh)<ref name="PMID19328897"/>. Mouse models showed that an absence of Raldh causes choanal atresia, resulting in respiratory distress and death of Raldh3 knockout mutants at birth<ref name="PMID14623956"><pubmed>14623956</pubmed></ref>.
|}
</table>

====Clinical Features====

[[File:Choanal atresia computed tomography 01.jpg|300px|thumb|right|Computed Tomography of Choanal Atresia]] Neonates are obligate nose breathers, hence neonatal nasal obstruction as seen in choanal atresia is a serious deformity. In order to avoid severe hypoxia and death, immediate diagnosis and intervention are key<ref name="PMID11232465"><pubmed>11232465<pubmed/></ref>. The severity of the clinical features of choanal atresia depends on the whether the obstruction is unilateral or bilateral <ref name="PMID19328897"/>.

'''Bilateral'''
* At birth present with ''asphyxia neonatorum'': pathological changes caused by hypoxia from affected respiration. A medical emergency requiring an oral airway tube or intubation then immediate surgical intervention<ref name="PMID19328897"/><ref name="PMID12567078"><pubmed>12567078<pubmed/></ref>
* Obvious airway obstruction <ref name="PMID19328897"/>
* Stridor, a harsh vibrating sound when breathing <ref name="PMID19328897"/>
* Paradoxical cyanosis: cyanosis is present in the infant at rest but improves with exertion such as crying <ref name="PMID19328897"/>

'''Unilateral'''
* Not as life threatening as bilateral choanal atresia; more often diagnosed in childhood than in infancy <ref name="PMID19328897"/><ref name="PMID12567078"/>
* Mucoid rhinorrhea, constant mucous fluid discharge from nose <ref name="PMID19328897"/><ref name="PMID12567078"/>
* Dysosmia, distorted olfaction <ref name="PMID12567078"/>
* Obstructive sleep apnea <ref name="PMID12567078"/>

------

===Kallmann Syndrome===
====Introduction and Epidemiology====
[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|500px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]Kallmann syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb (OB) is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract. As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

'''Genetic Factors'''
In Kallmann syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations in six genes and the proteins they encode (see table below) have been attributed to Kallmann syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis of Kallmann Syndrome are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>. Note that CHD7 can also be mutated in Kallmann's syndrome patients, though these individuals tend to have additional features that are part of the CHARGE syndrome phenotype described in the section on [[#Choanal Atresia|'''Choanal Atresia''']]<ref name="PMID19021638"><pubmed>19021638</pubmed></ref>.

<table>
{| width=100%
|-bgcolor="#FF9900"
| width=9%|'''Gene'''
| width=20%|'''Mode of Inheritance'''
| width=50%|'''Role in Kallman’s Syndrome'''
|-bgcolor="#FFFF99"
| '''KAL1'''
| X-linked
| KAL1 normally encodes glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
|-bgcolor="#FFCC66"
| '''FGFR1 (KAL2)'''
| Autosomal-dominant <ref name="PMID20117945"/>
| FGFR1 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/> <ref name="PMID12627230"><pubmed>12627230</pubmed></ref>. When absent, Kallmann syndrome arises due to agenesis or digenesis of the olfactory bulb and failure of GnRH neuronal development and migration.
|-bgcolor="#FFFF99"
| '''FGF8'''
| Autosomal-dominant <ref name="PMID20117945"/>
| Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation. Absence produces similar phenotype to KAL2 mutation<ref name="PMID20117945"/>.
|-bgcolor="#FFCC66"
| '''PROKR2 (KAL3)'''
| Monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID20389090"><pubmed>20389090</pubmed></ref><ref name="PMID18826963"><pubmed>18826963</pubmed></ref>.
| Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"/>.. However, the exact role in Kallmann syndrome has yet to be clarified<ref name="PMID18826963"/>..
|-bgcolor="#FFFF99"
| '''PROK2 (KAL4)'''
| Hypothesised to have mendelian autosomal recessive transmission in addition to oligogenic transmission<ref name="PMID20389090"/>.
| Encodes the PROKR2 ligand<ref name="PMID18826963"/>. When PROK2 mutated, the ligand is not expressed preventing prokineticin receptor-2 activation; this produces similar effects to PROKR2 abnormalities.

|}
</table>

====Clinical Features====

Kallmann Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell<ref name="PMID22882983"/>. There exists additional characteristics that are not specific to Kallmann syndrome but may aid in correct diagnosis of this particular HH<ref name="PMID22882983"/>. The following characteristics of Kallmann syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* Cryptorchidism: Failure of one or both testes to migrate into the scrotum during male foetus development.
* Gynaecomastia: The development of abnormal mammary glands in males characterised by enlarged breasts.
* Amennorhoea: the absence of menstruation, in females

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification
* Unilateral renal [[#Glossary |'''aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* Pes cavus: Also called clawfoot, refers to a deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. <ref name="PMID16932275"/>
* Neurological symptoms
** Synkinesia: Patients can conduct voluntary movements, however, with accompanied involuntary muscular movements.
** Abnormalities in eye movement
** Cerebellar ataxia: Reduced control over muscle coordination arising from defects or damage to the cerebellum.
** Evoked horizontal nystagmus: fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.
** Sensorineural deafness
** Spatial attentional abnormalities
** Spastic paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>

===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmanb syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
[http://www.ncbi.nlm.nih.gov/pubmed/21543621 Forni PE et al.]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]][http://www.ncbi.nlm.nih.gov/pubmed/21943152 ''The dual origin of the peripheral olfactory system''] also investigated the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
[http://www.ncbi.nlm.nih.gov/pubmed/22906231 Shaker T. et al.] published a paper in August this year looking into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular section of the research looked to determine whether Neurog1 and Neurog2 were required for olfactory bulb development. A loss-of-function technique was utilised to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
[[File:Absence_of_CSFR1_Impacts_Normal_Development_of_Brain_Architecture.jpg|200px|thumb|left|'''Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development'''- Absence of CSF-1R results in perturbed brain architecture.]]A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cribiform Plate''': The inferior surface of the ethmoid bone which roofs the nasal cavities.

'''Ectoderm:''' The outermost layer of the trilaminar embryo. Differentiates to form structures including the epidermis and neural tissue.

'''Epiblast:''' The collective term for embryonic mesoderm and ectoderm before differentiation

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Frontonasal Prominence''': An ectodermal expansive process that arises during the third week of embryonic development and forms the forehead and nasal bridge.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nasal Fin''': A plate-like ectodermal structure that forms between the medial and lateral prominences that thins to the form the oronasal membrane.

'''Nasal Septum''': Separates the left and right airways of the nose into nostrils. It is made up of the perpendicular plate of ethmoid bone, the vomer bone, cartilage and the crest of the maxillary and palatine bones.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Olfactory Placode''': A thickened area of ectoderm on the frontonasal prominence which contributes to the development of the olfactory sensory system.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones. A rudimentary organ in humans.

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

[http://kallmanns.org/ The Kallmann's Syndrome Organisation]

==Additional images==
<gallery>
Image:Vomeronasal_Organ_position.jpg
Image:Nasal_placode_diagram.jpeg
Image:Olfactory_bulb_and_epithelium.png
Image:Olfactory_epithelium.jpg
Image:New_olfactory_bulb.jpg
Image:Choanal_atresia_computed_tomography_01.jpg
Image:Normal_Neuronal_Migration_into_the_Olfactory_Bulb_Compared_to_Kallmann's_Syndrome.jpg
Image:Neural_crest-derived_cells_in_the_embryonic_olfactory_epithelium.jpg
Image:Absence_of_CSFR1_Impacts_Normal_Development_of_Brain_Architecture.jpg
Image:week4.jpg
Image:week5.jpg
Image:week6.jpg
Image:week7.jpg
</gallery>

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-10-02T23:43:29Z

Z3374215: /* Pathophysiology */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
|[[File:Vomeronasal Organ position.jpg|thumb|right|200px|alt=Alt|''Vomeronasal Organ position''']]

Discovery of [[#Glossary|'''Vomeronasal organ''']] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|'''hypogonadism''']] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|'''epiblast''']], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of [[#Glossary|'''ectoderm''']]<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|'''cribriform plate''']]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia and midline anatomic defects) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for revealing the large number of genes involved in odour reception. <ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|350px|right|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]
[http://www.example.com Nasal Cavity]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells. <ref name="PMID7143026"><pubmed>7143026</pubmed></ref>.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.<ref name="PMID17468753 "><pubmed>17468753 </pubmed></ref>.

[http://www.ncbi.nlm.nih.gov/books/NBK10896/ Olfactory epithelium]
==== Olfactory Bulb ====

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined. The olfactory bulb is essential for olfaction as it transmits information from the olfactory epithelium and up to the brain. The bulb receives input from olfactory nerves which constitutes the axons of olfactory receptor neurons. <ref name="PMID12951145 "><pubmed>12951145</pubmed></ref>.

Structures known as glomeruli form by a number of olfactory axons joining together such that each glomerulus obtain information from olfactory neurons which have the identical odour receptors. These glomeruli structures are also surrounded by dendrites belonging to mitral cells which transmit electrical signals to the olfactory cortex in the brain.<ref name="PMID16269360"><pubmed>16269360</pubmed></ref>.

==== Cribiform plate ====

The cribiform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groove allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha. If the cribriform plate happens to get fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose. <ref name="PMID11226964"><pubmed>11226964</pubmed></ref>.

== Normal Function ==

===Olfactory Signal Transduction===

[[File:New olfactory bulb.jpg|450px|thumb|right|Olfactory Bulb]]

Olfactory Signal Transduction is initiated by any substance that emit molecules known as odours. The olfactory transduction is dependent upon the dissolving of these odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors in order for chemical signals to be converted into electrical signals. The transformation into electrical signal is essential for signal transduction for the brain to perceive the initial odourants as smell. <ref name="PMID18066954"><pubmed>18066954</pubmed></ref>.

When odorant molecules bind to receptors in olfactory epithelium, a G protein coupled receptors known as G(αolf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP (cAMP). In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions by binding to and opening cyclic nucleotide gated ion channel to travel through the membrane and enter the cell. <ref name="PMID19652915"><pubmed>19652915</pubmed></ref>. The main effect of ion entry into the cell is depolarisation, and activation of chloride channels resulting in greater depolarisation by the efflux of chloride ions. If the depolarization in the cell is great enough, an action potential is generated on the axon of the receptor cell and transferred to the brain through the olfactory bulb.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

Similar to other G-protein mediated pathways, the olfactory sensory neuron is exposed to negative feedback by the cAMP cascade activated by odours. The negative feedback loop has been discovered to be responsible for the adaption of odours and deactivation of response after exposure for a certain period of time. <ref name="PMID19804753"><pubmed>19804753</pubmed></ref>.

[http://www.youtube.com/watch?v=dIDBG-UPRUI&feature=related| Olfactory Signal Transduction]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
* All five facial swellings form initially surrounding the stomodeum.

* The [[#Glossary |'''frontonasal prominence''']] is the facial swelling which gives rise to [[#Glossary | '''olfactory placodes''']]. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>.

An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. Mesencephalic region produced neural crest cells which contributed to the frontonasal mass.<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>

* These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

* Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

* Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref name="PMID15454774"><pubmed>15454774</pubmed></ref>
||
[[File:week4.jpg|200px|thumb|right|Embryo at week 4]]
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

* As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

* The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit as the face folds, dividing the frontonasal prominence into the lateral and medial nasal processes.These pits deepen as the surrounding mesenchyme proliferates to form '''primordial nasal sacs''' which grow dorsally but remain ventral to the forebrain. <ref name="PMID15454774"><pubmed>15454774</pubmed></ref> These sacs are separated from the oral cavity via the '''oronasal membrane'''.

* '''Glial cells''': Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref>

||
[[File:Week5.jpg|200px|thumb|right|Embryo at week 5]]
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
* '''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

* The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and [[#Glossary |'''nasal septum''']].<ref name="PMID438867"><pubmed>438867</pubmed></ref>

* The oronasal membrane ruptures by the end of this week, allowing communication between the nasal and oral cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* '''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
The superior, middle, and inferior nasal conchae develop as the lateral walls of the nasal cavities proliferate and so elevate.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref name="PMID15454774"><pubmed>15454774</pubmed></ref>

* '''Vomeronasal Organ Primordium''': Visible as epithelial swellings on the lower medial aspect of the nasal pit.<ref name="PMID9712194"><pubmed>9712194</pubmed></ref>. The anterior part can be seen as an indentation and the posterior part can be seen as continuous epithelium with the nasal septum. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* [[#Glossary |'''Vomeronasal Organ''']]: The VNP's are no longer visible but are instead in the form of bilateral tubes with well delineated lumens, that open anteriorly into the nasal cavity.<ref name="PMID11117628"><pubmed>11117628</pubmed></ref> The VNO epithelium is thicker than respiratory epithelium up until 12 weeks when the respiratory epithelium overtakes in thickness<ref name="PMID11117628"><pubmed>11117628</pubmed></ref>. The medial sides of the VNO's proliferate into thicker, microvillous sensory epithelium while the the lateral sides are thinner, receptor-free, ciliated epithelium. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

||
[[File:Week6.jpg|200px|thumb|right|Embryo at week 6]]
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
* '''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla.
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* '''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse to form the primary palate.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, [[#Glossary |'''Nasal fin.''']]<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* '''Secondary Palate''': Formed as the two palatine shelves extend medially and fuse at the midline at the primary palate.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The lining of the olfactory placode differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

- '''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

- '''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

- '''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

* At the end of the 7th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated [[#Glossary |'''cribriform plate''']]. <ref name="PMID15454774"><pubmed>15454774</pubmed></ref>

* [[#Glossary |'''Olfactory bulb''']] growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* [[#Glossary |'''Olfactory nerve''']] formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.<ref name="PMID11117628"><pubmed>11117628</pubmed></ref>
As a result, the CNS olfactory tracts look stalk-like.

* '''Olfactory nerve''': the '''olfactory tract''' and bulb together.

* By this stage the olfactory nerve is divided into a medial and lateral plexus. The medial plexus receives the VNO axon strands which are directed towards the caudal part of the olfactory bulb. Meanwhile the lateral plexus receives axon elongation from the olfactory epithelium and is directed towards the lateral edge of the olfactory bulb. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* Migration of Gonadotropin Releasing hormone along the vomeronasal nerve between weeks 6 to 8- plays a part in hypothalamus development.<ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
[[File:Week7.jpg|200px|thumb|right|Embryo at week 7]]
|- bgcolor="#BCD4E6"
|''Week 8/Fetal development''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
* '''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

* '''VNO:''' At this stage, the number of ciliated VNO epithelial cells increases into the late fetal period whilst the number of receptor cells decreases. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>
The degeneration of the VNO is noted by the closure of the duct and formation of a cyst like structure in the nasal septum. However, in most adults, the duct is left opened to a certain degree.<ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

* During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
||
[[#Normal Function |'''See normally developed sensory structures of olfaction''']]

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann Syndrome|'''Kallmann Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

------

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by narrowing or complete obliteration of the nasal aperture by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. The following models have been proposed to explain how choanal atresia may occur in the developing human.

<table>
{| width=100%
|-bgcolor="#FF9900 "
| width=20%|'''Risk Factor Model'''
| width=80%|'''Description'''
|-bgcolor="#FFFF99"
| ''' Embryonic'''
| Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence":
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter<ref name="PMID19328897"/>
* Abnormal persistence of mesoderm, resulting in adhesions in the nasochoanal region<ref name="PMID19328897"/>
* Misdirection of neural crest cell migration <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>
|-bgcolor="#FFCC66"
| '''Genetic'''
|
* A study <ref name="PMID3679682"><pubmed> 3679682</pubmed></ref> reported that 30% of children with choanal atresia had '''CHARGE Syndrome''' which stands for: Coloboma, Heart defect, Atresia Choanae, Retarded Growth and development, Genital hypoplasia, Ear anomalies or deafness <ref name="PMID19328897"/>.
* CHD7 gene on chromosome 8q12.1 found in 64% of CHARGE syndrome patients though its function is unknown. <ref name="PMID16155193"><pubmed>16155193</pubmed></ref>
|-bgcolor="#FFFF99"
| '''Molecular'''
|
* '''Thionamides and Hyperthyroidism''': A number of studies reported an increased incidence of choanal atresia in babies of hyperthyroid mothers treated with thionamides<ref name="PMID3688031"><pubmed>3688031</pubmed></ref><ref name="PMID9450891"><pubmed>9450891</pubmed></ref><ref name="PMID18698631"><pubmed>18698631</pubmed></ref>. The majority of hyperthyroid mothers had elevated levels of stimulating antibody for the thyrotropin receptor<ref name="PMID19328897"/>. Human studies and animal models have shown that elevated thyrotropin alters the expression of the growth factor FGF, FGF receptors and angiogenic factors which may play a role in development of choanal atresia<ref name="PMID12746216"><pubmed>18698631</pubmed></ref><ref name="PMID11397875"><pubmed>11397875</pubmed></ref>. However, further research is required in order to determine the exact mechanisms involved.

* '''Retinoic Acid''': Retinoic acid is the product of vitamin A metabolism by retinaldehyde dehydrogenase (Raldh)<ref name="PMID19328897"/>. Mouse models showed that an absence of Raldh causes choanal atresia, resulting in respiratory distress and death of Raldh3 knockout mutants at birth<ref name="PMID14623956"><pubmed>14623956</pubmed></ref>.
|}
</table>

====Clinical Features====

[[File:Choanal atresia computed tomography 01.jpg|300px|thumb|right|Computed Tomography of Choanal Atresia]] Neonates are obligate nose breathers, hence neonatal nasal obstruction as seen in choanal atresia is a serious deformity. In order to avoid severe hypoxia and death, immediate diagnosis and intervention are key<ref name="PMID11232465"><pubmed>11232465<pubmed/></ref>. The severity of the clinical features of choanal atresia depends on the whether the obstruction is unilateral or bilateral <ref name="PMID19328897"/>.

'''Bilateral'''
* At birth present with ''asphyxia neonatorum'': pathological changes caused by hypoxia from affected respiration. A medical emergency requiring an oral airway tube or intubation then immediate surgical intervention<ref name="PMID19328897"/><ref name="PMID12567078"><pubmed>12567078<pubmed/></ref>
* Obvious airway obstruction <ref name="PMID19328897"/>
* Stridor, a harsh vibrating sound when breathing <ref name="PMID19328897"/>
* Paradoxical cyanosis: cyanosis is present in the infant at rest but improves with exertion such as crying <ref name="PMID19328897"/>

'''Unilateral'''
* Not as life threatening as bilateral choanal atresia; more often diagnosed in childhood than in infancy <ref name="PMID19328897"/><ref name="PMID12567078"/>
* Mucoid rhinorrhea, constant mucous fluid discharge from nose <ref name="PMID19328897"/><ref name="PMID12567078"/>
* Dysosmia, distorted olfaction <ref name="PMID12567078"/>
* Obstructive sleep apnea <ref name="PMID12567078"/>

------

===Kallmann Syndrome===
====Introduction and Epidemiology====
[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|500px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]Kallmann syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb (OB) is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract. As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

'''Genetic Factors'''
In Kallmann syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations in six genes and the proteins they encode (see table below) have been attributed to Kallmann syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis of Kallmann Syndrome are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>. Note that CHD7 can also be mutated in Kallmann's syndrome patients, though these individuals tend to have additional features that are part of the CHARGE syndrome phenotype described in the section on [[#Choanal Atresia|'''Choanal Atresia''']]<ref name="PMID19021638"><pubmed>19021638</pubmed></ref>.

<table>
{| width=100%
|-bgcolor="#FF9900"
| width=9%|'''Gene'''
| width=20%|'''Mode of Inheritance'''
| width=50%|'''Role in Kallman’s Syndrome'''
|-bgcolor="#FFFF99"
| '''KAL1'''
| X-linked
| KAL1 normally encodes glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
|-bgcolor="#FFCC66"
| '''FGFR1 (KAL2)'''
| Autosomal-dominant <ref name="PMID20117945"/>
| FGFR1 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/> <ref name="PMID12627230"><pubmed>12627230</pubmed></ref>. When absent, Kallmann syndrome arises due to agenesis or digenesis of the olfactory bulb and failure of GnRH neuronal development and migration.
|-bgcolor="#FFFF99"
| '''FGF8'''
| Autosomal-dominant <ref name="PMID20117945"/>
| Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation. Absence produces similar phenotype to KAL2 mutation<ref name="PMID20117945"/>.
|-bgcolor="#FFCC66"
| '''PROKR2 (KAL3)'''
| Monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID20389090"><pubmed>20389090</pubmed></ref><ref name="PMID18826963"><pubmed>18826963</pubmed></ref>.
| Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"/>.. However, the exact role in Kallmann syndrome has yet to be clarified<ref name="PMID18826963"/>..
|-bgcolor="#FFFF99"
| '''PROK2 (KAL4)'''
| Hypothesised to have mendelian autosomal recessive transmission in addition to oligogenic transmission<ref name="PMID20389090"/>.
| Encodes the PROKR2 ligand<ref name="PMID18826963"/>. When PROK2 mutated, the ligand is not expressed preventing prokineticin receptor-2 activation; this produces similar effects to PROKR2 abnormalities.

|}
</table>

====Clinical Features====

Kallmann Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell<ref name="PMID22882983"/>. There exists additional characteristics that are not specific to Kallmann syndrome but may aid in correct diagnosis of this particular HH<ref name="PMID22882983"/>. The following characteristics of Kallmann syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* Cryptorchidism: Failure of one or both testes to migrate into the scrotum during male foetus development.
* Gynaecomastia: The development of abnormal mammary glands in males characterised by enlarged breasts.
* Amennorhoea: the absence of menstruation, in females

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification
* Unilateral renal [[#Glossary |'''aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* Pes cavus: Also called clawfoot, refers to a deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. <ref name="PMID16932275"/>
* Neurological symptoms
** Synkinesia: Patients can conduct voluntary movements, however, with accompanied involuntary muscular movements.
** Abnormalities in eye movement
** Cerebellar ataxia: Reduced control over muscle coordination arising from defects or damage to the cerebellum.
** Evoked horizontal nystagmus: fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.
** Sensorineural deafness
** Spatial attentional abnormalities
** Spastic paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>

===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmanb syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
[http://www.ncbi.nlm.nih.gov/pubmed/21543621 Forni PE et al.]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]][http://www.ncbi.nlm.nih.gov/pubmed/21943152 ''The dual origin of the peripheral olfactory system''] also investigated the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
[http://www.ncbi.nlm.nih.gov/pubmed/22906231 Shaker T. et al.] published a paper in August this year looking into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular section of the research looked to determine whether Neurog1 and Neurog2 were required for olfactory bulb development. A loss-of-function technique was utilised to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
[[File:Absence_of_CSFR1_Impacts_Normal_Development_of_Brain_Architecture.jpg|200px|thumb|left|'''Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development'''- Absence of CSF-1R results in perturbed brain architecture.]]A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cribiform Plate''': The inferior surface of the ethmoid bone which roofs the nasal cavities.

'''Ectoderm:''' The outermost layer of the trilaminar embryo. Differentiates to form structures including the epidermis and neural tissue.

'''Epiblast:''' The collective term for embryonic mesoderm and ectoderm before differentiation

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Frontonasal Prominence''': An ectodermal expansive process that arises during the third week of embryonic development and forms the forehead and nasal bridge.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nasal Fin''': A plate-like ectodermal structure that forms between the medial and lateral prominences that thins to the form the oronasal membrane.

'''Nasal Septum''': Separates the left and right airways of the nose into nostrils. It is made up of the perpendicular plate of ethmoid bone, the vomer bone, cartilage and the crest of the maxillary and palatine bones.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Olfactory Placode''': A thickened area of ectoderm on the frontonasal prominence which contributes to the development of the olfactory sensory system.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

[http://kallmanns.org/ The Kallmann's Syndrome Organisation]

==Additional images==
<gallery>
Image:Vomeronasal_Organ_position.jpg
Image:Nasal_placode_diagram.jpeg
Image:Olfactory_bulb_and_epithelium.png
Image:Olfactory_epithelium.jpg
Image:New_olfactory_bulb.jpg
Image:Choanal_atresia_computed_tomography_01.jpg
Image:Normal_Neuronal_Migration_into_the_Olfactory_Bulb_Compared_to_Kallmann's_Syndrome.jpg
Image:Neural_crest-derived_cells_in_the_embryonic_olfactory_epithelium.jpg
Image:Absence_of_CSFR1_Impacts_Normal_Development_of_Brain_Architecture.jpg
Image:week4.jpg
Image:week5.jpg
Image:week6.jpg
Image:week7.jpg
</gallery>

{{External Links}}

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

----

{{2012Projects}}

User:Z3374215

2012-10-02T10:38:28Z

Z3374215: /* Lab 9 */

==Lab Attendance==

Lab 1 --[[User:Z3374215|Z3374215]] 11:49, 25 July 2012 (EST)

Lab 2 --[[User:Z3374215|Z3374215]] 10:06, 1 August 2012 (EST)

Lab 3 --[[User:Z3374215|Z3374215]] 10:06, 8 August 2012 (EST)

Lab 4 --[[User:Z3374215|Z3374215]] 12:01, 15 August 2012 (EST)

Lab 5 --[[User:Z3374215|Z3374215]] 10:05, 22 August 2012 (EST)

Lab 6 --[[User:Z3374215|Z3374215]] 10:08, 29 August 2012 (EST)

Lab 7 --[[User:Z3374215|Z3374215]] 10:14, 12 September 2012 (EST)

Lab 8 --[[User:Z3374215|Z3374215]] 11:34, 19 September 2012 (EST)

Lab 9 --[[User:Z3374215|Z3374215]] 10:10, 26 September 2012 (EST)

==Lab 1 Assessment==
'''1) Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.'''

The Nobel Prize for physiology or medicine in 2010 was awarded to Robert G. Edwards for his efforts in the development of In Vitro fertilization. Robert G. Edwards developed the idea of In Vitro fertilization since the 1950s. He first made fundamental discoveries in the life cycles of human eggs and the optimal time for fertilization before pairing with a gynecologist, Patrick Steptoe, and eventually seeing to the successful birth of an IVF baby in 1978. <ref>http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html</ref>.

'''2) Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).
'''
"The relative contributions of propulsive forces and receptor-ligand binding forces during early contact between spermatozoa and zona pellucida of oocyte" was published by the Journal of Theoretical Biology in Nov. 2011 <ref name= 'PMID22100500"><pubmed>22100500</pubmed></ref>. This report discusses the two main ways in which spermatozoa penetrate the zona pellucida of oocytes. The sperm utilize propulsive forces to assist in penetration. This is achieved through the motion of the flagella. The other factor important to penetration is the binding of sperm to ligands on the surface of the zona pellucida of the oocyte (ZP3). The report addresses the question of which of the cofactors is most imperative to the successful fertilization of the oocyte. A biomechanical model of the sperm-oocyte process was developed. It predicted that during early penetration the propulsive forces were stronger than the biochemical ligand binding. It was also predicted that the constant movement and overpowering force of the propulsion of sperm would make binding to ZP3 ligands difficult, making the large number of ZP3 receptors on the head of the sperm significantly important at this early stage.

===References===
<references/>

==Lab 2 Assessment==
'''1) Upload an image from a journal source relating to fertilization or the first 2 weeks of development as demonstrated in the practical class. Including in the image “Summary” window: An image name as a section heading, Any further description of what the image shows, A subsection labeled “Reference” and under this the original image source, appropriate reference and all copyright information and finally a template indicating that this is a student image.'''

'''Image:''' Expression of Endometrial CD98 in implantation<ref name:"PMID20976164"><pubmed>20976164</pubmed></ref>
[[Image:Expression of Endometrial CD98 in implantation.png|thumb|center|alt=Alt|Expression of Endometrial CD98 in implantation]]

'''2) Identify a protein associated with the implantation process, including a brief description of the protein's role (1-2 paragraphs).'''

A study has identified trophinin as a protein important to the adhesion implantation process. It is believed to be a single intrinsic protein that spans the membrane due to hydrophobic tendencies. This molecule can adhere without the aid of calcium unlike many cell adhesion molecules. Trophinin molecules bind with other trophinin molecule in trans structure on the cell surface. Immunostaining showed that antigens specific to the trophinin molecule can be found in both trophoblast cells and in the maternal epithelium near implantation sites of the embryo. The protein has been found to be encoded in the short arm of the X chromosome. It is also present in the mouse, sheep and bovine, along with monotremes and marsupials. It appears that the binding of the trophectoderm (consists of trophoblasts and is the connection between the blastocyst and the maternal cells) is essential to invasion and proliferation of cells. In embryonic cells trophinin induces and promotes invasion and proliferation. In maternal cells the same protein promotes apoptosis (controlled cell death) so as to allow the acceptance of the embryo. Therefore it is a dual signalling molecule. <ref name="PMID22717627"><pubmed>22717627</pubmed></ref>

===Reference===
<references/>

==Lab 3 Assessment==

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

The gestational age refers to the time since the last normal menstruation period<ref>Moore, K.L., 2011 ''The Developing Human'' 9th ed. W.B. Saunders</ref>. Whereas post-fertilisation age is calculated from the time of fertilization. There can be confusion between the terms espcially as gestational age is two weeks longer than post-fertilisation age<ref name:"PMID"15520122"><pubmed>15520122,</pubmed></ref>. Although in itself the term gestation age is confusing as there is no actual conceptus in until fertilisation but it is accepted by clinicians through widespread use<ref name:"PMID16006453"><pubmed>16006453</pubmed></ref>. As exact post-fetilisation age would be difficult to determine gestational age is used clinically. In assisted reproduction cases post-fertilisation age can be accurately determined but 2 weeks are generally added to age for ease of understanding<ref name:"PMID"15520122"><pubmed>15520122,</pubmed></ref>.

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

Somites form the dermis of the dorsal epithelium, skeletal muscles and some connective tissue, specifically, the vertebrae and ribs.<ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Paraxial Mesoderm: The Somites and Their Derivatives. Available from: http://www.ncbi.nlm.nih.gov/books/NBK10085/</ref>

===References===
<references/>

==Lab 4 Assessment==
'''1) Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.'''
Prenatal placental biopsy an invasive diagnostic technique for genetic abnormalities (such as trisomy 21) in the fetus. A karyotype is constructed allowing analysis of the chromosomes. It is used in the second and third trimester of pregnancy to confirm suspected malformations. Placental biopsies are sonographically guided<ref name:"PMID2712602"><pubmed>2712602</pubmed></ref>.
Chorionic villus testing is another invasive technique carried out transcervically in the first trimester to detect inherited disorders such as haemophilia <ref name:"PMID22250892"><pubmed>22250892</pubmed></ref>

'''2) Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''
Mesenchymal stem cells derived from the human umbilical cord have been used as a therapeutic treatment for neuromyelitis optica. Neuromyelitis optica is an autoimmune inflammatory disease that effects the optic nerve and spinal cord. Stem cells have been seen to provide differentiation potential to neural cells, secrete necessary factors and help regulate immunological function.
Five patients were treated with stem cell injections and then monitored for 18 months to analyse the effects both adverse and any improvements. Four out of the five patients gained some relief following treatment. Signs and symptoms decreased and the frequency of relapse was lessened. The neurological lesions also decreased in volume and severity as seen by MRI. The paper summarised that human umbilical cord stem cells were an appropriate therapy technique<ref name:"PMID22873728"><pubmed>22873728</pubmed></ref>.

===References===
<references/>

==Lab 7 Assessment==
'''1. (a) Provide a one sentence definition of a muscle satellite cell'''

Muscle satellite cells are progenitor cells and are involved in muscle growth and repair as they can induce regenerated muscle and additional satellite cells<ref name:”PMID12757751”><pubmed>12757751</pubmed></ref>

'''(b) In one paragraph, briefly discuss two examples of when satellite cells are activated.'''

A study investigating exercised induced satellite cell activation in skeletal muscle of growing and mature rats concluded that satellite cells are activated by acute sessions of prolonged eccentric exercise. It also concluded that exercise affected the proliferation of young mitotically active satellite cells<ref name:”PMID3693217”><pubmed>3693217</pubmed></ref>. Satellite cells are also activated when damage occurs. A study indicated that two variants of the IGF-I gene are necessary for activation of satellite cells. The study examined induced lesions to the anterior tibialis muscle of rats. The results showed that one variant of the gene which gives rise to a growth factor, MGF, is initially produced after injury and it activates satellite cells then IGF-IEa is expressed to maintain the repair process <ref>M Hill1, A Wernig, G Goldspink '''Muscle satellite (stem) cell activation during local tissue injury and repair''' Journal of Anatomy:2003, 203(1);89-99</ref>

'''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.'''

In a study involving 12 human patients suffering from spinal cord injuries a section of the vastus lateralis muscle was biopsied at 3 intervals within the first 6month following injury. From 6-24 weeks after injury they showed 27-56% atrophy of Type I, IIa and IIax+IIx fibers. There was increased conversion between muscle types, type IIa decreased and type IIax+IIx increased. However there was little change in proportion of tpye I fibers during this period<ref name:"PMID9887150"><pubmed>9887150</pubmed></ref>

===Reference===
<references/>

==Lab 8 Assessment - Peer Review==
===Vision===
The layout of the page is relatively good. If anything it appears little too image heavy at the moment. On the note of images, the referencing is good but don't forget to include the student template note with each image. The inclusion of some student drawn images in great to see but it might be an idea to make the labels larger as they are hard to read. The use of subheadings is great, a really logically well set out page. The references need a bit of work, some are spread sporadically throughout the page and some in the references section just list the URL along with the error on reference number 13.

The introductory is brief but alright. However the first two images are largely similar, not sure why both need to be included. Perhaps if possible it would be nice to link each of the main anatomical bullet points you have listed in your introduction to their associated developmental paragraph further down the page.

The History of development is coming along nicely but perhaps would be easier to read if it was in the format of a table. Also the Atlas of the Development of Man needs to be properly referenced with the author in the reference section. It would be nice to have some information relating to the pictures uploaded in this section.

The section on Development is well done and it is interesting to look at the individual development of each structure. It might be an idea to include some more references to when each structural development occurs. Current Research really needs some more content. The glossary is a nice addition and helpful.

===Somatosensory===
This page has made good use of subheadings ensuring that the main topics are easily accessible from the contents box. The project appears a little text heavy, it may help to include some other images. Also don't forget to add the student template note on the student drawn image. The reference list at the end is not particularly extensive. Perhaps this can be worked on by collecting the loose references in the text and adding them to the final reference section. Overall some sections of the page seem to have little to with embryology and more focused on adult function.

The introduction, while good, seems to lack any original voice, rather seeming to consist almost entirely of research done by others. The referencing in this section is also confusing with (Lagercrantz, Hanson, Evrard & Rodeck, 2001) being listed before any text. Referencing in this format also makes the page seem like a report or essay rather than a web page. There is also mention of a picture that does not exist. The historic section is brief and rather hard to digest as it is just a chunk of text. Perhaps putting this information into a table and developing it a little would help here.

The section on Central Somatosensory Differentiation was particularly well done. The inclusion of the student drawn image making all the difference. The general structure of this section is also commendable.

The subtitles "Touch", "Pain", "Heat/Cold" and "Pressure" are somewhat abrupt and don't particularly indicate what the section is discussing. This section in particular could do with the addition of some images. The information under Touch could perhaps be a little more heavily researched but is generally well written. Breaking the Pain section into some smaller paragraphs could be useful. The Hot/Cold and Pressure sections are well done excepting the random references to some articles.

Current research section could do with some more information. There are several words throughout the content that could do with being linked to an explanation in the glossary such as the "dorsal column-medial lemniscal system". The external links section is a good addition but it might be helpful to explain more clearly what each links to, especially the last three.

===Taste===
Initially the page seems to have a good balance between text and diagrams/photographs. However the figures included are not properly labelled once you click on the file and some of them don't appear to have any copyright information included. Some of the pictures could do with being a bit smaller as they take up a large proportion of the page. The student drawn image of the tongue is particularly impressive but does still need to have the student template included. The references seem limited in comparison to other groups perhaps suggesting a lack of depth or variety of research. There also appears to be a coding problem relating to reference number 5. The general layout and use of subheadings is great. It may be useful to link the words in the glossary to their occurrence in the text.

The introductory paragraphs are very well written. They are easy to understand and interesting and give a good overview of how taste functions. Similarly the section on taste map is well written clearly explaining the neurological factors associated with taste. However the presence of the picture in isolation is confusing as it is representing an the old method of taste association. Perhaps this would be resolved if a diagram of the newer taste map was also included. Also you say that the old taste map has been disproved by recent research but that research is not referenced. In fact it appears that very little of that section is referenced. The section on cortical areas is well done.

The timeline of developmental processes is good, the table an easy visual format and the information concise and effective. The only point of contention would be the direct quote in Wk8-9 which seems out of place in comparison to the remainder of the entries which are nicely paraphrased. The history section is similarly well done being extensive and comprehensive. That is excepting some Pub Med references which are just placed in the text rather than in the reference list at the bottom. While interesting and well written the part detailing the Adult Tongue and Taste Buds seems out of place in a embryology course.

The sections on the effect of gene expression on the formation of taste abnormalities and current research are good. However it may be useful to put the information regarding each picture as a caption rather than plain text.

It will be interesting to see what is put in the section "Image Gallery"

===Abnormal Vision===
Your introduction is relatively well written and the brief explanation of new terms such as microphthalmia was particularly useful. Perhaps it would be possible to break the text into two paragraphs to make reading easier.
It is really good to see a section included about normal eye development as it provides a basis of understanding for the remainder of the page. Concise and to the point and not too complex, it's great. Only suggestion would be to place it in a table perhaps with each Carnegie stage a new entry.

Layout of abnormalities is very logical covering the main areas of developmental abnormalities. However it is slightly confusing that immediately under the title Abnormal Lens Development more information on normal development is given. Allocating the defects to their associated individual genes is good but perhaps instead of a dotpoint a subheading would be of more use. The actual information is clearly and effectively written. The inclusion of the pictures clearly illustrates the abnormalities but their placement is a little odd. Perhaps they are too large. The captions on the pictures are appropriate and the pictures are appropriately referenced and it is great that the link to the picture contains more information.

Under the title "Ocular Manifestations" perhaps indicate what the two sections are, just so the following on sections make sense and don't appear disjointed. The sections on the genetic caused abnormalities is fascinating and very well written. The timeline included in the information about Leber Congenital Amaurosis is particularly interesting. The spacing in the section on genes associated with Anophthalmia and Microphthalmia appears slightly strange. The figures included are particularly illustrative and appropriate. Similarly the section on environmentally caused abnormalities is really well written and interesting.

Perhaps a more extensive section on current research could be included. If possible, link the words in the glossary to where they appeared in the text. This is the coding if you don't have it [[#Glossary|'''Words for Glossary''']]. Just add that in place of the word when you first mention it in the text. The citing and referencing is really well done. It also shows a great depth of research. The figures/photographs so far included are brilliant but the inclusion of a student drawn diagram somewhere if possible would be effective. Also try and fix the general layout of the project, possibly including some more subheadings. In general the content relates to the the course and is pitched at an appropriate level. Hope this helps.

===Hearing===
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.

==Lab 9==
'''1) Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

Hes1 is a target gene associated with notch signalling (a type of cell signaling pathway). It affects the proliferation and differentiation of progenitor cells. mic lacking the Hes 1 gene were observed to analyse the genes involvement in thyroid analyses. In a normal mouse the gene was expressed after E9.5. Hes1 lacking mice presented a smaller thyroid surface area at all stages and the fusion of the median anlage and ultimobranchial bodies was significantly delayed. It was suggested that the Hes1 gene is important for control of final number of thyrocyte and C-cell progenitors and ensuring adequate differentiation and endocrine function of these cells<ref name = "PMID21364918"><pubmed>21364918</pubmed></ref>.

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

Teeth form from the ectodermal layer of the oral cavity in association with the surrounding mesoderm. Specialised ectodermal cells termed ameloblasts secrete enamel. Mesenchymal mesoderm is responsible for other dental structures. Other specialised cells involved in tooth formation include odonoblasts and cementoblasts.<ref>John F. Neas, 2002 ''Human Anatomy Fourth Edition'', Chapter 4, Benjamin Cummings. Sourced from: http://cwx.prenhall.com/bookbind/pubbooks/martini10/chapter4/custom3/deluxe-content.html </ref>

===References===
<references/>

User:Z3374215

2012-10-02T10:37:48Z

Z3374215: /* Lab 9 */

==Lab Attendance==

Lab 1 --[[User:Z3374215|Z3374215]] 11:49, 25 July 2012 (EST)

Lab 2 --[[User:Z3374215|Z3374215]] 10:06, 1 August 2012 (EST)

Lab 3 --[[User:Z3374215|Z3374215]] 10:06, 8 August 2012 (EST)

Lab 4 --[[User:Z3374215|Z3374215]] 12:01, 15 August 2012 (EST)

Lab 5 --[[User:Z3374215|Z3374215]] 10:05, 22 August 2012 (EST)

Lab 6 --[[User:Z3374215|Z3374215]] 10:08, 29 August 2012 (EST)

Lab 7 --[[User:Z3374215|Z3374215]] 10:14, 12 September 2012 (EST)

Lab 8 --[[User:Z3374215|Z3374215]] 11:34, 19 September 2012 (EST)

Lab 9 --[[User:Z3374215|Z3374215]] 10:10, 26 September 2012 (EST)

==Lab 1 Assessment==
'''1) Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.'''

The Nobel Prize for physiology or medicine in 2010 was awarded to Robert G. Edwards for his efforts in the development of In Vitro fertilization. Robert G. Edwards developed the idea of In Vitro fertilization since the 1950s. He first made fundamental discoveries in the life cycles of human eggs and the optimal time for fertilization before pairing with a gynecologist, Patrick Steptoe, and eventually seeing to the successful birth of an IVF baby in 1978. <ref>http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html</ref>.

'''2) Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).
'''
"The relative contributions of propulsive forces and receptor-ligand binding forces during early contact between spermatozoa and zona pellucida of oocyte" was published by the Journal of Theoretical Biology in Nov. 2011 <ref name= 'PMID22100500"><pubmed>22100500</pubmed></ref>. This report discusses the two main ways in which spermatozoa penetrate the zona pellucida of oocytes. The sperm utilize propulsive forces to assist in penetration. This is achieved through the motion of the flagella. The other factor important to penetration is the binding of sperm to ligands on the surface of the zona pellucida of the oocyte (ZP3). The report addresses the question of which of the cofactors is most imperative to the successful fertilization of the oocyte. A biomechanical model of the sperm-oocyte process was developed. It predicted that during early penetration the propulsive forces were stronger than the biochemical ligand binding. It was also predicted that the constant movement and overpowering force of the propulsion of sperm would make binding to ZP3 ligands difficult, making the large number of ZP3 receptors on the head of the sperm significantly important at this early stage.

===References===
<references/>

==Lab 2 Assessment==
'''1) Upload an image from a journal source relating to fertilization or the first 2 weeks of development as demonstrated in the practical class. Including in the image “Summary” window: An image name as a section heading, Any further description of what the image shows, A subsection labeled “Reference” and under this the original image source, appropriate reference and all copyright information and finally a template indicating that this is a student image.'''

'''Image:''' Expression of Endometrial CD98 in implantation<ref name:"PMID20976164"><pubmed>20976164</pubmed></ref>
[[Image:Expression of Endometrial CD98 in implantation.png|thumb|center|alt=Alt|Expression of Endometrial CD98 in implantation]]

'''2) Identify a protein associated with the implantation process, including a brief description of the protein's role (1-2 paragraphs).'''

A study has identified trophinin as a protein important to the adhesion implantation process. It is believed to be a single intrinsic protein that spans the membrane due to hydrophobic tendencies. This molecule can adhere without the aid of calcium unlike many cell adhesion molecules. Trophinin molecules bind with other trophinin molecule in trans structure on the cell surface. Immunostaining showed that antigens specific to the trophinin molecule can be found in both trophoblast cells and in the maternal epithelium near implantation sites of the embryo. The protein has been found to be encoded in the short arm of the X chromosome. It is also present in the mouse, sheep and bovine, along with monotremes and marsupials. It appears that the binding of the trophectoderm (consists of trophoblasts and is the connection between the blastocyst and the maternal cells) is essential to invasion and proliferation of cells. In embryonic cells trophinin induces and promotes invasion and proliferation. In maternal cells the same protein promotes apoptosis (controlled cell death) so as to allow the acceptance of the embryo. Therefore it is a dual signalling molecule. <ref name="PMID22717627"><pubmed>22717627</pubmed></ref>

===Reference===
<references/>

==Lab 3 Assessment==

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

The gestational age refers to the time since the last normal menstruation period<ref>Moore, K.L., 2011 ''The Developing Human'' 9th ed. W.B. Saunders</ref>. Whereas post-fertilisation age is calculated from the time of fertilization. There can be confusion between the terms espcially as gestational age is two weeks longer than post-fertilisation age<ref name:"PMID"15520122"><pubmed>15520122,</pubmed></ref>. Although in itself the term gestation age is confusing as there is no actual conceptus in until fertilisation but it is accepted by clinicians through widespread use<ref name:"PMID16006453"><pubmed>16006453</pubmed></ref>. As exact post-fetilisation age would be difficult to determine gestational age is used clinically. In assisted reproduction cases post-fertilisation age can be accurately determined but 2 weeks are generally added to age for ease of understanding<ref name:"PMID"15520122"><pubmed>15520122,</pubmed></ref>.

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

Somites form the dermis of the dorsal epithelium, skeletal muscles and some connective tissue, specifically, the vertebrae and ribs.<ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Paraxial Mesoderm: The Somites and Their Derivatives. Available from: http://www.ncbi.nlm.nih.gov/books/NBK10085/</ref>

===References===
<references/>

==Lab 4 Assessment==
'''1) Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.'''
Prenatal placental biopsy an invasive diagnostic technique for genetic abnormalities (such as trisomy 21) in the fetus. A karyotype is constructed allowing analysis of the chromosomes. It is used in the second and third trimester of pregnancy to confirm suspected malformations. Placental biopsies are sonographically guided<ref name:"PMID2712602"><pubmed>2712602</pubmed></ref>.
Chorionic villus testing is another invasive technique carried out transcervically in the first trimester to detect inherited disorders such as haemophilia <ref name:"PMID22250892"><pubmed>22250892</pubmed></ref>

'''2) Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''
Mesenchymal stem cells derived from the human umbilical cord have been used as a therapeutic treatment for neuromyelitis optica. Neuromyelitis optica is an autoimmune inflammatory disease that effects the optic nerve and spinal cord. Stem cells have been seen to provide differentiation potential to neural cells, secrete necessary factors and help regulate immunological function.
Five patients were treated with stem cell injections and then monitored for 18 months to analyse the effects both adverse and any improvements. Four out of the five patients gained some relief following treatment. Signs and symptoms decreased and the frequency of relapse was lessened. The neurological lesions also decreased in volume and severity as seen by MRI. The paper summarised that human umbilical cord stem cells were an appropriate therapy technique<ref name:"PMID22873728"><pubmed>22873728</pubmed></ref>.

===References===
<references/>

==Lab 7 Assessment==
'''1. (a) Provide a one sentence definition of a muscle satellite cell'''

Muscle satellite cells are progenitor cells and are involved in muscle growth and repair as they can induce regenerated muscle and additional satellite cells<ref name:”PMID12757751”><pubmed>12757751</pubmed></ref>

'''(b) In one paragraph, briefly discuss two examples of when satellite cells are activated.'''

A study investigating exercised induced satellite cell activation in skeletal muscle of growing and mature rats concluded that satellite cells are activated by acute sessions of prolonged eccentric exercise. It also concluded that exercise affected the proliferation of young mitotically active satellite cells<ref name:”PMID3693217”><pubmed>3693217</pubmed></ref>. Satellite cells are also activated when damage occurs. A study indicated that two variants of the IGF-I gene are necessary for activation of satellite cells. The study examined induced lesions to the anterior tibialis muscle of rats. The results showed that one variant of the gene which gives rise to a growth factor, MGF, is initially produced after injury and it activates satellite cells then IGF-IEa is expressed to maintain the repair process <ref>M Hill1, A Wernig, G Goldspink '''Muscle satellite (stem) cell activation during local tissue injury and repair''' Journal of Anatomy:2003, 203(1);89-99</ref>

'''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.'''

In a study involving 12 human patients suffering from spinal cord injuries a section of the vastus lateralis muscle was biopsied at 3 intervals within the first 6month following injury. From 6-24 weeks after injury they showed 27-56% atrophy of Type I, IIa and IIax+IIx fibers. There was increased conversion between muscle types, type IIa decreased and type IIax+IIx increased. However there was little change in proportion of tpye I fibers during this period<ref name:"PMID9887150"><pubmed>9887150</pubmed></ref>

===Reference===
<references/>

==Lab 8 Assessment - Peer Review==
===Vision===
The layout of the page is relatively good. If anything it appears little too image heavy at the moment. On the note of images, the referencing is good but don't forget to include the student template note with each image. The inclusion of some student drawn images in great to see but it might be an idea to make the labels larger as they are hard to read. The use of subheadings is great, a really logically well set out page. The references need a bit of work, some are spread sporadically throughout the page and some in the references section just list the URL along with the error on reference number 13.

The introductory is brief but alright. However the first two images are largely similar, not sure why both need to be included. Perhaps if possible it would be nice to link each of the main anatomical bullet points you have listed in your introduction to their associated developmental paragraph further down the page.

The History of development is coming along nicely but perhaps would be easier to read if it was in the format of a table. Also the Atlas of the Development of Man needs to be properly referenced with the author in the reference section. It would be nice to have some information relating to the pictures uploaded in this section.

The section on Development is well done and it is interesting to look at the individual development of each structure. It might be an idea to include some more references to when each structural development occurs. Current Research really needs some more content. The glossary is a nice addition and helpful.

===Somatosensory===
This page has made good use of subheadings ensuring that the main topics are easily accessible from the contents box. The project appears a little text heavy, it may help to include some other images. Also don't forget to add the student template note on the student drawn image. The reference list at the end is not particularly extensive. Perhaps this can be worked on by collecting the loose references in the text and adding them to the final reference section. Overall some sections of the page seem to have little to with embryology and more focused on adult function.

The introduction, while good, seems to lack any original voice, rather seeming to consist almost entirely of research done by others. The referencing in this section is also confusing with (Lagercrantz, Hanson, Evrard & Rodeck, 2001) being listed before any text. Referencing in this format also makes the page seem like a report or essay rather than a web page. There is also mention of a picture that does not exist. The historic section is brief and rather hard to digest as it is just a chunk of text. Perhaps putting this information into a table and developing it a little would help here.

The section on Central Somatosensory Differentiation was particularly well done. The inclusion of the student drawn image making all the difference. The general structure of this section is also commendable.

The subtitles "Touch", "Pain", "Heat/Cold" and "Pressure" are somewhat abrupt and don't particularly indicate what the section is discussing. This section in particular could do with the addition of some images. The information under Touch could perhaps be a little more heavily researched but is generally well written. Breaking the Pain section into some smaller paragraphs could be useful. The Hot/Cold and Pressure sections are well done excepting the random references to some articles.

Current research section could do with some more information. There are several words throughout the content that could do with being linked to an explanation in the glossary such as the "dorsal column-medial lemniscal system". The external links section is a good addition but it might be helpful to explain more clearly what each links to, especially the last three.

===Taste===
Initially the page seems to have a good balance between text and diagrams/photographs. However the figures included are not properly labelled once you click on the file and some of them don't appear to have any copyright information included. Some of the pictures could do with being a bit smaller as they take up a large proportion of the page. The student drawn image of the tongue is particularly impressive but does still need to have the student template included. The references seem limited in comparison to other groups perhaps suggesting a lack of depth or variety of research. There also appears to be a coding problem relating to reference number 5. The general layout and use of subheadings is great. It may be useful to link the words in the glossary to their occurrence in the text.

The introductory paragraphs are very well written. They are easy to understand and interesting and give a good overview of how taste functions. Similarly the section on taste map is well written clearly explaining the neurological factors associated with taste. However the presence of the picture in isolation is confusing as it is representing an the old method of taste association. Perhaps this would be resolved if a diagram of the newer taste map was also included. Also you say that the old taste map has been disproved by recent research but that research is not referenced. In fact it appears that very little of that section is referenced. The section on cortical areas is well done.

The timeline of developmental processes is good, the table an easy visual format and the information concise and effective. The only point of contention would be the direct quote in Wk8-9 which seems out of place in comparison to the remainder of the entries which are nicely paraphrased. The history section is similarly well done being extensive and comprehensive. That is excepting some Pub Med references which are just placed in the text rather than in the reference list at the bottom. While interesting and well written the part detailing the Adult Tongue and Taste Buds seems out of place in a embryology course.

The sections on the effect of gene expression on the formation of taste abnormalities and current research are good. However it may be useful to put the information regarding each picture as a caption rather than plain text.

It will be interesting to see what is put in the section "Image Gallery"

===Abnormal Vision===
Your introduction is relatively well written and the brief explanation of new terms such as microphthalmia was particularly useful. Perhaps it would be possible to break the text into two paragraphs to make reading easier.
It is really good to see a section included about normal eye development as it provides a basis of understanding for the remainder of the page. Concise and to the point and not too complex, it's great. Only suggestion would be to place it in a table perhaps with each Carnegie stage a new entry.

Layout of abnormalities is very logical covering the main areas of developmental abnormalities. However it is slightly confusing that immediately under the title Abnormal Lens Development more information on normal development is given. Allocating the defects to their associated individual genes is good but perhaps instead of a dotpoint a subheading would be of more use. The actual information is clearly and effectively written. The inclusion of the pictures clearly illustrates the abnormalities but their placement is a little odd. Perhaps they are too large. The captions on the pictures are appropriate and the pictures are appropriately referenced and it is great that the link to the picture contains more information.

Under the title "Ocular Manifestations" perhaps indicate what the two sections are, just so the following on sections make sense and don't appear disjointed. The sections on the genetic caused abnormalities is fascinating and very well written. The timeline included in the information about Leber Congenital Amaurosis is particularly interesting. The spacing in the section on genes associated with Anophthalmia and Microphthalmia appears slightly strange. The figures included are particularly illustrative and appropriate. Similarly the section on environmentally caused abnormalities is really well written and interesting.

Perhaps a more extensive section on current research could be included. If possible, link the words in the glossary to where they appeared in the text. This is the coding if you don't have it [[#Glossary|'''Words for Glossary''']]. Just add that in place of the word when you first mention it in the text. The citing and referencing is really well done. It also shows a great depth of research. The figures/photographs so far included are brilliant but the inclusion of a student drawn diagram somewhere if possible would be effective. Also try and fix the general layout of the project, possibly including some more subheadings. In general the content relates to the the course and is pitched at an appropriate level. Hope this helps.

===Hearing===
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.

==Lab 9==
'''1) Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

Hes1 is a target gene associated with notch signalling (a type of cell signaling pathway). It affects the proliferation and differentiation of progenitor cells. mic lacking the Hes 1 gene were observed to analyse the genes involvement in thyroid analyses. In a normal mouse the gene was expressed after E9.5. Hes1 lacking mice presented a smaller thyroid surface area at all stages and the fusion of the median anlage and ultimobranchial bodies was significantly delayed. It was suggested that the Hes1 gene is important for control of final number of thyrocyte and C-cell progenitors and ensuring adequate differentiation and endocrine function of these cells<ref name = "PMID21364918"><pubmed>21364918</pubmed></ref>.

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

Teeth form from the ectodermal layer of the oral cavity in association with the surrounding mesoderm. Specialised ectodermal cells termed ameloblasts secrete enamel. Mesenchymal mesoderm is responsible for other dental structures. Other specialised cells involved in tooth formation include odonoblasts and cementoblasts.<ref>John F. Neas, 2002 ''Human Anatomy Fourth Edition'', Chapter 4, Benjamin Cummings </ref>

===References===
<references/>

User:Z3374215

2012-10-02T09:36:29Z

Z3374215: /* Lab 9 */

==Lab Attendance==

Lab 1 --[[User:Z3374215|Z3374215]] 11:49, 25 July 2012 (EST)

Lab 2 --[[User:Z3374215|Z3374215]] 10:06, 1 August 2012 (EST)

Lab 3 --[[User:Z3374215|Z3374215]] 10:06, 8 August 2012 (EST)

Lab 4 --[[User:Z3374215|Z3374215]] 12:01, 15 August 2012 (EST)

Lab 5 --[[User:Z3374215|Z3374215]] 10:05, 22 August 2012 (EST)

Lab 6 --[[User:Z3374215|Z3374215]] 10:08, 29 August 2012 (EST)

Lab 7 --[[User:Z3374215|Z3374215]] 10:14, 12 September 2012 (EST)

Lab 8 --[[User:Z3374215|Z3374215]] 11:34, 19 September 2012 (EST)

Lab 9 --[[User:Z3374215|Z3374215]] 10:10, 26 September 2012 (EST)

==Lab 1 Assessment==
'''1) Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.'''

The Nobel Prize for physiology or medicine in 2010 was awarded to Robert G. Edwards for his efforts in the development of In Vitro fertilization. Robert G. Edwards developed the idea of In Vitro fertilization since the 1950s. He first made fundamental discoveries in the life cycles of human eggs and the optimal time for fertilization before pairing with a gynecologist, Patrick Steptoe, and eventually seeing to the successful birth of an IVF baby in 1978. <ref>http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html</ref>.

'''2) Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).
'''
"The relative contributions of propulsive forces and receptor-ligand binding forces during early contact between spermatozoa and zona pellucida of oocyte" was published by the Journal of Theoretical Biology in Nov. 2011 <ref name= 'PMID22100500"><pubmed>22100500</pubmed></ref>. This report discusses the two main ways in which spermatozoa penetrate the zona pellucida of oocytes. The sperm utilize propulsive forces to assist in penetration. This is achieved through the motion of the flagella. The other factor important to penetration is the binding of sperm to ligands on the surface of the zona pellucida of the oocyte (ZP3). The report addresses the question of which of the cofactors is most imperative to the successful fertilization of the oocyte. A biomechanical model of the sperm-oocyte process was developed. It predicted that during early penetration the propulsive forces were stronger than the biochemical ligand binding. It was also predicted that the constant movement and overpowering force of the propulsion of sperm would make binding to ZP3 ligands difficult, making the large number of ZP3 receptors on the head of the sperm significantly important at this early stage.

===References===
<references/>

==Lab 2 Assessment==
'''1) Upload an image from a journal source relating to fertilization or the first 2 weeks of development as demonstrated in the practical class. Including in the image “Summary” window: An image name as a section heading, Any further description of what the image shows, A subsection labeled “Reference” and under this the original image source, appropriate reference and all copyright information and finally a template indicating that this is a student image.'''

'''Image:''' Expression of Endometrial CD98 in implantation<ref name:"PMID20976164"><pubmed>20976164</pubmed></ref>
[[Image:Expression of Endometrial CD98 in implantation.png|thumb|center|alt=Alt|Expression of Endometrial CD98 in implantation]]

'''2) Identify a protein associated with the implantation process, including a brief description of the protein's role (1-2 paragraphs).'''

A study has identified trophinin as a protein important to the adhesion implantation process. It is believed to be a single intrinsic protein that spans the membrane due to hydrophobic tendencies. This molecule can adhere without the aid of calcium unlike many cell adhesion molecules. Trophinin molecules bind with other trophinin molecule in trans structure on the cell surface. Immunostaining showed that antigens specific to the trophinin molecule can be found in both trophoblast cells and in the maternal epithelium near implantation sites of the embryo. The protein has been found to be encoded in the short arm of the X chromosome. It is also present in the mouse, sheep and bovine, along with monotremes and marsupials. It appears that the binding of the trophectoderm (consists of trophoblasts and is the connection between the blastocyst and the maternal cells) is essential to invasion and proliferation of cells. In embryonic cells trophinin induces and promotes invasion and proliferation. In maternal cells the same protein promotes apoptosis (controlled cell death) so as to allow the acceptance of the embryo. Therefore it is a dual signalling molecule. <ref name="PMID22717627"><pubmed>22717627</pubmed></ref>

===Reference===
<references/>

==Lab 3 Assessment==

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

The gestational age refers to the time since the last normal menstruation period<ref>Moore, K.L., 2011 ''The Developing Human'' 9th ed. W.B. Saunders</ref>. Whereas post-fertilisation age is calculated from the time of fertilization. There can be confusion between the terms espcially as gestational age is two weeks longer than post-fertilisation age<ref name:"PMID"15520122"><pubmed>15520122,</pubmed></ref>. Although in itself the term gestation age is confusing as there is no actual conceptus in until fertilisation but it is accepted by clinicians through widespread use<ref name:"PMID16006453"><pubmed>16006453</pubmed></ref>. As exact post-fetilisation age would be difficult to determine gestational age is used clinically. In assisted reproduction cases post-fertilisation age can be accurately determined but 2 weeks are generally added to age for ease of understanding<ref name:"PMID"15520122"><pubmed>15520122,</pubmed></ref>.

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

Somites form the dermis of the dorsal epithelium, skeletal muscles and some connective tissue, specifically, the vertebrae and ribs.<ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Paraxial Mesoderm: The Somites and Their Derivatives. Available from: http://www.ncbi.nlm.nih.gov/books/NBK10085/</ref>

===References===
<references/>

==Lab 4 Assessment==
'''1) Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.'''
Prenatal placental biopsy an invasive diagnostic technique for genetic abnormalities (such as trisomy 21) in the fetus. A karyotype is constructed allowing analysis of the chromosomes. It is used in the second and third trimester of pregnancy to confirm suspected malformations. Placental biopsies are sonographically guided<ref name:"PMID2712602"><pubmed>2712602</pubmed></ref>.
Chorionic villus testing is another invasive technique carried out transcervically in the first trimester to detect inherited disorders such as haemophilia <ref name:"PMID22250892"><pubmed>22250892</pubmed></ref>

'''2) Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''
Mesenchymal stem cells derived from the human umbilical cord have been used as a therapeutic treatment for neuromyelitis optica. Neuromyelitis optica is an autoimmune inflammatory disease that effects the optic nerve and spinal cord. Stem cells have been seen to provide differentiation potential to neural cells, secrete necessary factors and help regulate immunological function.
Five patients were treated with stem cell injections and then monitored for 18 months to analyse the effects both adverse and any improvements. Four out of the five patients gained some relief following treatment. Signs and symptoms decreased and the frequency of relapse was lessened. The neurological lesions also decreased in volume and severity as seen by MRI. The paper summarised that human umbilical cord stem cells were an appropriate therapy technique<ref name:"PMID22873728"><pubmed>22873728</pubmed></ref>.

===References===
<references/>

==Lab 7 Assessment==
'''1. (a) Provide a one sentence definition of a muscle satellite cell'''

Muscle satellite cells are progenitor cells and are involved in muscle growth and repair as they can induce regenerated muscle and additional satellite cells<ref name:”PMID12757751”><pubmed>12757751</pubmed></ref>

'''(b) In one paragraph, briefly discuss two examples of when satellite cells are activated.'''

A study investigating exercised induced satellite cell activation in skeletal muscle of growing and mature rats concluded that satellite cells are activated by acute sessions of prolonged eccentric exercise. It also concluded that exercise affected the proliferation of young mitotically active satellite cells<ref name:”PMID3693217”><pubmed>3693217</pubmed></ref>. Satellite cells are also activated when damage occurs. A study indicated that two variants of the IGF-I gene are necessary for activation of satellite cells. The study examined induced lesions to the anterior tibialis muscle of rats. The results showed that one variant of the gene which gives rise to a growth factor, MGF, is initially produced after injury and it activates satellite cells then IGF-IEa is expressed to maintain the repair process <ref>M Hill1, A Wernig, G Goldspink '''Muscle satellite (stem) cell activation during local tissue injury and repair''' Journal of Anatomy:2003, 203(1);89-99</ref>

'''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.'''

In a study involving 12 human patients suffering from spinal cord injuries a section of the vastus lateralis muscle was biopsied at 3 intervals within the first 6month following injury. From 6-24 weeks after injury they showed 27-56% atrophy of Type I, IIa and IIax+IIx fibers. There was increased conversion between muscle types, type IIa decreased and type IIax+IIx increased. However there was little change in proportion of tpye I fibers during this period<ref name:"PMID9887150"><pubmed>9887150</pubmed></ref>

===Reference===
<references/>

==Lab 8 Assessment - Peer Review==
===Vision===
The layout of the page is relatively good. If anything it appears little too image heavy at the moment. On the note of images, the referencing is good but don't forget to include the student template note with each image. The inclusion of some student drawn images in great to see but it might be an idea to make the labels larger as they are hard to read. The use of subheadings is great, a really logically well set out page. The references need a bit of work, some are spread sporadically throughout the page and some in the references section just list the URL along with the error on reference number 13.

The introductory is brief but alright. However the first two images are largely similar, not sure why both need to be included. Perhaps if possible it would be nice to link each of the main anatomical bullet points you have listed in your introduction to their associated developmental paragraph further down the page.

The History of development is coming along nicely but perhaps would be easier to read if it was in the format of a table. Also the Atlas of the Development of Man needs to be properly referenced with the author in the reference section. It would be nice to have some information relating to the pictures uploaded in this section.

The section on Development is well done and it is interesting to look at the individual development of each structure. It might be an idea to include some more references to when each structural development occurs. Current Research really needs some more content. The glossary is a nice addition and helpful.

===Somatosensory===
This page has made good use of subheadings ensuring that the main topics are easily accessible from the contents box. The project appears a little text heavy, it may help to include some other images. Also don't forget to add the student template note on the student drawn image. The reference list at the end is not particularly extensive. Perhaps this can be worked on by collecting the loose references in the text and adding them to the final reference section. Overall some sections of the page seem to have little to with embryology and more focused on adult function.

The introduction, while good, seems to lack any original voice, rather seeming to consist almost entirely of research done by others. The referencing in this section is also confusing with (Lagercrantz, Hanson, Evrard & Rodeck, 2001) being listed before any text. Referencing in this format also makes the page seem like a report or essay rather than a web page. There is also mention of a picture that does not exist. The historic section is brief and rather hard to digest as it is just a chunk of text. Perhaps putting this information into a table and developing it a little would help here.

The section on Central Somatosensory Differentiation was particularly well done. The inclusion of the student drawn image making all the difference. The general structure of this section is also commendable.

The subtitles "Touch", "Pain", "Heat/Cold" and "Pressure" are somewhat abrupt and don't particularly indicate what the section is discussing. This section in particular could do with the addition of some images. The information under Touch could perhaps be a little more heavily researched but is generally well written. Breaking the Pain section into some smaller paragraphs could be useful. The Hot/Cold and Pressure sections are well done excepting the random references to some articles.

Current research section could do with some more information. There are several words throughout the content that could do with being linked to an explanation in the glossary such as the "dorsal column-medial lemniscal system". The external links section is a good addition but it might be helpful to explain more clearly what each links to, especially the last three.

===Taste===
Initially the page seems to have a good balance between text and diagrams/photographs. However the figures included are not properly labelled once you click on the file and some of them don't appear to have any copyright information included. Some of the pictures could do with being a bit smaller as they take up a large proportion of the page. The student drawn image of the tongue is particularly impressive but does still need to have the student template included. The references seem limited in comparison to other groups perhaps suggesting a lack of depth or variety of research. There also appears to be a coding problem relating to reference number 5. The general layout and use of subheadings is great. It may be useful to link the words in the glossary to their occurrence in the text.

The introductory paragraphs are very well written. They are easy to understand and interesting and give a good overview of how taste functions. Similarly the section on taste map is well written clearly explaining the neurological factors associated with taste. However the presence of the picture in isolation is confusing as it is representing an the old method of taste association. Perhaps this would be resolved if a diagram of the newer taste map was also included. Also you say that the old taste map has been disproved by recent research but that research is not referenced. In fact it appears that very little of that section is referenced. The section on cortical areas is well done.

The timeline of developmental processes is good, the table an easy visual format and the information concise and effective. The only point of contention would be the direct quote in Wk8-9 which seems out of place in comparison to the remainder of the entries which are nicely paraphrased. The history section is similarly well done being extensive and comprehensive. That is excepting some Pub Med references which are just placed in the text rather than in the reference list at the bottom. While interesting and well written the part detailing the Adult Tongue and Taste Buds seems out of place in a embryology course.

The sections on the effect of gene expression on the formation of taste abnormalities and current research are good. However it may be useful to put the information regarding each picture as a caption rather than plain text.

It will be interesting to see what is put in the section "Image Gallery"

===Abnormal Vision===
Your introduction is relatively well written and the brief explanation of new terms such as microphthalmia was particularly useful. Perhaps it would be possible to break the text into two paragraphs to make reading easier.
It is really good to see a section included about normal eye development as it provides a basis of understanding for the remainder of the page. Concise and to the point and not too complex, it's great. Only suggestion would be to place it in a table perhaps with each Carnegie stage a new entry.

Layout of abnormalities is very logical covering the main areas of developmental abnormalities. However it is slightly confusing that immediately under the title Abnormal Lens Development more information on normal development is given. Allocating the defects to their associated individual genes is good but perhaps instead of a dotpoint a subheading would be of more use. The actual information is clearly and effectively written. The inclusion of the pictures clearly illustrates the abnormalities but their placement is a little odd. Perhaps they are too large. The captions on the pictures are appropriate and the pictures are appropriately referenced and it is great that the link to the picture contains more information.

Under the title "Ocular Manifestations" perhaps indicate what the two sections are, just so the following on sections make sense and don't appear disjointed. The sections on the genetic caused abnormalities is fascinating and very well written. The timeline included in the information about Leber Congenital Amaurosis is particularly interesting. The spacing in the section on genes associated with Anophthalmia and Microphthalmia appears slightly strange. The figures included are particularly illustrative and appropriate. Similarly the section on environmentally caused abnormalities is really well written and interesting.

Perhaps a more extensive section on current research could be included. If possible, link the words in the glossary to where they appeared in the text. This is the coding if you don't have it [[#Glossary|'''Words for Glossary''']]. Just add that in place of the word when you first mention it in the text. The citing and referencing is really well done. It also shows a great depth of research. The figures/photographs so far included are brilliant but the inclusion of a student drawn diagram somewhere if possible would be effective. Also try and fix the general layout of the project, possibly including some more subheadings. In general the content relates to the the course and is pitched at an appropriate level. Hope this helps.

===Hearing===
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.

===Lab 9===
'''1) Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

Hes1 is a target gene associated with notch signalling (a type of cell signaling pathway). It affects the proliferation and differentiation of progenitor cells. mic lacking the Hes 1 gene were observed to analyse the genes involvement in thyroid analyses. In a normal mouse the gene was expressed after E9.5. Hes1 lacking mice presented a smaller thyroid surface area at all stages and the fusion of the median anlage and ultimobranchial bodies was significantly delayed. It was suggested that the Hes1 gene is important for control of final number of thyrocyte and C-cell progenitors and ensuring adequate differentiation and endocrine function of these cells<ref name = "PMID21364918"><pubmed>21364918</pubmed></ref>.

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

===References===
<references/>

User:Z3374215

2012-10-02T09:35:28Z

Z3374215: /* Lab 9 */

==Lab Attendance==

Lab 1 --[[User:Z3374215|Z3374215]] 11:49, 25 July 2012 (EST)

Lab 2 --[[User:Z3374215|Z3374215]] 10:06, 1 August 2012 (EST)

Lab 3 --[[User:Z3374215|Z3374215]] 10:06, 8 August 2012 (EST)

Lab 4 --[[User:Z3374215|Z3374215]] 12:01, 15 August 2012 (EST)

Lab 5 --[[User:Z3374215|Z3374215]] 10:05, 22 August 2012 (EST)

Lab 6 --[[User:Z3374215|Z3374215]] 10:08, 29 August 2012 (EST)

Lab 7 --[[User:Z3374215|Z3374215]] 10:14, 12 September 2012 (EST)

Lab 8 --[[User:Z3374215|Z3374215]] 11:34, 19 September 2012 (EST)

Lab 9 --[[User:Z3374215|Z3374215]] 10:10, 26 September 2012 (EST)

==Lab 1 Assessment==
'''1) Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.'''

The Nobel Prize for physiology or medicine in 2010 was awarded to Robert G. Edwards for his efforts in the development of In Vitro fertilization. Robert G. Edwards developed the idea of In Vitro fertilization since the 1950s. He first made fundamental discoveries in the life cycles of human eggs and the optimal time for fertilization before pairing with a gynecologist, Patrick Steptoe, and eventually seeing to the successful birth of an IVF baby in 1978. <ref>http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html</ref>.

'''2) Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).
'''
"The relative contributions of propulsive forces and receptor-ligand binding forces during early contact between spermatozoa and zona pellucida of oocyte" was published by the Journal of Theoretical Biology in Nov. 2011 <ref name= 'PMID22100500"><pubmed>22100500</pubmed></ref>. This report discusses the two main ways in which spermatozoa penetrate the zona pellucida of oocytes. The sperm utilize propulsive forces to assist in penetration. This is achieved through the motion of the flagella. The other factor important to penetration is the binding of sperm to ligands on the surface of the zona pellucida of the oocyte (ZP3). The report addresses the question of which of the cofactors is most imperative to the successful fertilization of the oocyte. A biomechanical model of the sperm-oocyte process was developed. It predicted that during early penetration the propulsive forces were stronger than the biochemical ligand binding. It was also predicted that the constant movement and overpowering force of the propulsion of sperm would make binding to ZP3 ligands difficult, making the large number of ZP3 receptors on the head of the sperm significantly important at this early stage.

===References===
<references/>

==Lab 2 Assessment==
'''1) Upload an image from a journal source relating to fertilization or the first 2 weeks of development as demonstrated in the practical class. Including in the image “Summary” window: An image name as a section heading, Any further description of what the image shows, A subsection labeled “Reference” and under this the original image source, appropriate reference and all copyright information and finally a template indicating that this is a student image.'''

'''Image:''' Expression of Endometrial CD98 in implantation<ref name:"PMID20976164"><pubmed>20976164</pubmed></ref>
[[Image:Expression of Endometrial CD98 in implantation.png|thumb|center|alt=Alt|Expression of Endometrial CD98 in implantation]]

'''2) Identify a protein associated with the implantation process, including a brief description of the protein's role (1-2 paragraphs).'''

A study has identified trophinin as a protein important to the adhesion implantation process. It is believed to be a single intrinsic protein that spans the membrane due to hydrophobic tendencies. This molecule can adhere without the aid of calcium unlike many cell adhesion molecules. Trophinin molecules bind with other trophinin molecule in trans structure on the cell surface. Immunostaining showed that antigens specific to the trophinin molecule can be found in both trophoblast cells and in the maternal epithelium near implantation sites of the embryo. The protein has been found to be encoded in the short arm of the X chromosome. It is also present in the mouse, sheep and bovine, along with monotremes and marsupials. It appears that the binding of the trophectoderm (consists of trophoblasts and is the connection between the blastocyst and the maternal cells) is essential to invasion and proliferation of cells. In embryonic cells trophinin induces and promotes invasion and proliferation. In maternal cells the same protein promotes apoptosis (controlled cell death) so as to allow the acceptance of the embryo. Therefore it is a dual signalling molecule. <ref name="PMID22717627"><pubmed>22717627</pubmed></ref>

===Reference===
<references/>

==Lab 3 Assessment==

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

The gestational age refers to the time since the last normal menstruation period<ref>Moore, K.L., 2011 ''The Developing Human'' 9th ed. W.B. Saunders</ref>. Whereas post-fertilisation age is calculated from the time of fertilization. There can be confusion between the terms espcially as gestational age is two weeks longer than post-fertilisation age<ref name:"PMID"15520122"><pubmed>15520122,</pubmed></ref>. Although in itself the term gestation age is confusing as there is no actual conceptus in until fertilisation but it is accepted by clinicians through widespread use<ref name:"PMID16006453"><pubmed>16006453</pubmed></ref>. As exact post-fetilisation age would be difficult to determine gestational age is used clinically. In assisted reproduction cases post-fertilisation age can be accurately determined but 2 weeks are generally added to age for ease of understanding<ref name:"PMID"15520122"><pubmed>15520122,</pubmed></ref>.

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

Somites form the dermis of the dorsal epithelium, skeletal muscles and some connective tissue, specifically, the vertebrae and ribs.<ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Paraxial Mesoderm: The Somites and Their Derivatives. Available from: http://www.ncbi.nlm.nih.gov/books/NBK10085/</ref>

===References===
<references/>

==Lab 4 Assessment==
'''1) Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.'''
Prenatal placental biopsy an invasive diagnostic technique for genetic abnormalities (such as trisomy 21) in the fetus. A karyotype is constructed allowing analysis of the chromosomes. It is used in the second and third trimester of pregnancy to confirm suspected malformations. Placental biopsies are sonographically guided<ref name:"PMID2712602"><pubmed>2712602</pubmed></ref>.
Chorionic villus testing is another invasive technique carried out transcervically in the first trimester to detect inherited disorders such as haemophilia <ref name:"PMID22250892"><pubmed>22250892</pubmed></ref>

'''2) Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''
Mesenchymal stem cells derived from the human umbilical cord have been used as a therapeutic treatment for neuromyelitis optica. Neuromyelitis optica is an autoimmune inflammatory disease that effects the optic nerve and spinal cord. Stem cells have been seen to provide differentiation potential to neural cells, secrete necessary factors and help regulate immunological function.
Five patients were treated with stem cell injections and then monitored for 18 months to analyse the effects both adverse and any improvements. Four out of the five patients gained some relief following treatment. Signs and symptoms decreased and the frequency of relapse was lessened. The neurological lesions also decreased in volume and severity as seen by MRI. The paper summarised that human umbilical cord stem cells were an appropriate therapy technique<ref name:"PMID22873728"><pubmed>22873728</pubmed></ref>.

===References===
<references/>

==Lab 7 Assessment==
'''1. (a) Provide a one sentence definition of a muscle satellite cell'''

Muscle satellite cells are progenitor cells and are involved in muscle growth and repair as they can induce regenerated muscle and additional satellite cells<ref name:”PMID12757751”><pubmed>12757751</pubmed></ref>

'''(b) In one paragraph, briefly discuss two examples of when satellite cells are activated.'''

A study investigating exercised induced satellite cell activation in skeletal muscle of growing and mature rats concluded that satellite cells are activated by acute sessions of prolonged eccentric exercise. It also concluded that exercise affected the proliferation of young mitotically active satellite cells<ref name:”PMID3693217”><pubmed>3693217</pubmed></ref>. Satellite cells are also activated when damage occurs. A study indicated that two variants of the IGF-I gene are necessary for activation of satellite cells. The study examined induced lesions to the anterior tibialis muscle of rats. The results showed that one variant of the gene which gives rise to a growth factor, MGF, is initially produced after injury and it activates satellite cells then IGF-IEa is expressed to maintain the repair process <ref>M Hill1, A Wernig, G Goldspink '''Muscle satellite (stem) cell activation during local tissue injury and repair''' Journal of Anatomy:2003, 203(1);89-99</ref>

'''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.'''

In a study involving 12 human patients suffering from spinal cord injuries a section of the vastus lateralis muscle was biopsied at 3 intervals within the first 6month following injury. From 6-24 weeks after injury they showed 27-56% atrophy of Type I, IIa and IIax+IIx fibers. There was increased conversion between muscle types, type IIa decreased and type IIax+IIx increased. However there was little change in proportion of tpye I fibers during this period<ref name:"PMID9887150"><pubmed>9887150</pubmed></ref>

===Reference===
<references/>

==Lab 8 Assessment - Peer Review==
===Vision===
The layout of the page is relatively good. If anything it appears little too image heavy at the moment. On the note of images, the referencing is good but don't forget to include the student template note with each image. The inclusion of some student drawn images in great to see but it might be an idea to make the labels larger as they are hard to read. The use of subheadings is great, a really logically well set out page. The references need a bit of work, some are spread sporadically throughout the page and some in the references section just list the URL along with the error on reference number 13.

The introductory is brief but alright. However the first two images are largely similar, not sure why both need to be included. Perhaps if possible it would be nice to link each of the main anatomical bullet points you have listed in your introduction to their associated developmental paragraph further down the page.

The History of development is coming along nicely but perhaps would be easier to read if it was in the format of a table. Also the Atlas of the Development of Man needs to be properly referenced with the author in the reference section. It would be nice to have some information relating to the pictures uploaded in this section.

The section on Development is well done and it is interesting to look at the individual development of each structure. It might be an idea to include some more references to when each structural development occurs. Current Research really needs some more content. The glossary is a nice addition and helpful.

===Somatosensory===
This page has made good use of subheadings ensuring that the main topics are easily accessible from the contents box. The project appears a little text heavy, it may help to include some other images. Also don't forget to add the student template note on the student drawn image. The reference list at the end is not particularly extensive. Perhaps this can be worked on by collecting the loose references in the text and adding them to the final reference section. Overall some sections of the page seem to have little to with embryology and more focused on adult function.

The introduction, while good, seems to lack any original voice, rather seeming to consist almost entirely of research done by others. The referencing in this section is also confusing with (Lagercrantz, Hanson, Evrard & Rodeck, 2001) being listed before any text. Referencing in this format also makes the page seem like a report or essay rather than a web page. There is also mention of a picture that does not exist. The historic section is brief and rather hard to digest as it is just a chunk of text. Perhaps putting this information into a table and developing it a little would help here.

The section on Central Somatosensory Differentiation was particularly well done. The inclusion of the student drawn image making all the difference. The general structure of this section is also commendable.

The subtitles "Touch", "Pain", "Heat/Cold" and "Pressure" are somewhat abrupt and don't particularly indicate what the section is discussing. This section in particular could do with the addition of some images. The information under Touch could perhaps be a little more heavily researched but is generally well written. Breaking the Pain section into some smaller paragraphs could be useful. The Hot/Cold and Pressure sections are well done excepting the random references to some articles.

Current research section could do with some more information. There are several words throughout the content that could do with being linked to an explanation in the glossary such as the "dorsal column-medial lemniscal system". The external links section is a good addition but it might be helpful to explain more clearly what each links to, especially the last three.

===Taste===
Initially the page seems to have a good balance between text and diagrams/photographs. However the figures included are not properly labelled once you click on the file and some of them don't appear to have any copyright information included. Some of the pictures could do with being a bit smaller as they take up a large proportion of the page. The student drawn image of the tongue is particularly impressive but does still need to have the student template included. The references seem limited in comparison to other groups perhaps suggesting a lack of depth or variety of research. There also appears to be a coding problem relating to reference number 5. The general layout and use of subheadings is great. It may be useful to link the words in the glossary to their occurrence in the text.

The introductory paragraphs are very well written. They are easy to understand and interesting and give a good overview of how taste functions. Similarly the section on taste map is well written clearly explaining the neurological factors associated with taste. However the presence of the picture in isolation is confusing as it is representing an the old method of taste association. Perhaps this would be resolved if a diagram of the newer taste map was also included. Also you say that the old taste map has been disproved by recent research but that research is not referenced. In fact it appears that very little of that section is referenced. The section on cortical areas is well done.

The timeline of developmental processes is good, the table an easy visual format and the information concise and effective. The only point of contention would be the direct quote in Wk8-9 which seems out of place in comparison to the remainder of the entries which are nicely paraphrased. The history section is similarly well done being extensive and comprehensive. That is excepting some Pub Med references which are just placed in the text rather than in the reference list at the bottom. While interesting and well written the part detailing the Adult Tongue and Taste Buds seems out of place in a embryology course.

The sections on the effect of gene expression on the formation of taste abnormalities and current research are good. However it may be useful to put the information regarding each picture as a caption rather than plain text.

It will be interesting to see what is put in the section "Image Gallery"

===Abnormal Vision===
Your introduction is relatively well written and the brief explanation of new terms such as microphthalmia was particularly useful. Perhaps it would be possible to break the text into two paragraphs to make reading easier.
It is really good to see a section included about normal eye development as it provides a basis of understanding for the remainder of the page. Concise and to the point and not too complex, it's great. Only suggestion would be to place it in a table perhaps with each Carnegie stage a new entry.

Layout of abnormalities is very logical covering the main areas of developmental abnormalities. However it is slightly confusing that immediately under the title Abnormal Lens Development more information on normal development is given. Allocating the defects to their associated individual genes is good but perhaps instead of a dotpoint a subheading would be of more use. The actual information is clearly and effectively written. The inclusion of the pictures clearly illustrates the abnormalities but their placement is a little odd. Perhaps they are too large. The captions on the pictures are appropriate and the pictures are appropriately referenced and it is great that the link to the picture contains more information.

Under the title "Ocular Manifestations" perhaps indicate what the two sections are, just so the following on sections make sense and don't appear disjointed. The sections on the genetic caused abnormalities is fascinating and very well written. The timeline included in the information about Leber Congenital Amaurosis is particularly interesting. The spacing in the section on genes associated with Anophthalmia and Microphthalmia appears slightly strange. The figures included are particularly illustrative and appropriate. Similarly the section on environmentally caused abnormalities is really well written and interesting.

Perhaps a more extensive section on current research could be included. If possible, link the words in the glossary to where they appeared in the text. This is the coding if you don't have it [[#Glossary|'''Words for Glossary''']]. Just add that in place of the word when you first mention it in the text. The citing and referencing is really well done. It also shows a great depth of research. The figures/photographs so far included are brilliant but the inclusion of a student drawn diagram somewhere if possible would be effective. Also try and fix the general layout of the project, possibly including some more subheadings. In general the content relates to the the course and is pitched at an appropriate level. Hope this helps.

===Hearing===
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.

===Lab 9===
'''1) Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

Hes1 is a target gene associated with notch signalling (a type of cell signaling pathway). It affects the proliferation and differentiation of progenitor cells. mic lacking the Hes 1 gene were observed to analyse the genes involvement in thyroid analyses. In a normal mouse the gene was expressed after E9.5. Hes1 lacking mice presented a smaller thyroid surface area at all stages and the fusion of the median anlage and ultimobranchial bodies was significantly delayed. It was suggested that the Hes1 gene is important for control of final number of thyrocyte and C-cell progenitors and ensuring adequate differentiation and endocrine function of these cells.

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

2012 Group Project 4

2012-10-02T09:17:18Z

Z3374215: /* Choanal Atresia */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
|[[File:Vomeronasal Organ position.jpg|thumb|right|200px|alt=Alt|''Vomeronasal Organ position''']]

Discovery of [[#Glossary|'''Vomeronasal organ''']] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|'''hypogonadism''']] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|'''epiblast''']], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of [[#Glossary|'''ectoderm''']]<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|'''cribriform plate''']]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia and midline anatomic defects) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for revealing the large number of genes involved in odour reception. <ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|350px|right|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]
[http://www.example.com Nasal Cavity]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells. <ref name="PMID7143026"><pubmed>7143026</pubmed></ref>.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.<ref name="PMID17468753 "><pubmed>17468753 </pubmed></ref>.

[http://www.ncbi.nlm.nih.gov/books/NBK10896/ Olfactory epithelium]
==== Olfactory Bulb ====

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined. The olfactory bulb is essential for olfaction as it transmits information from the olfactory epithelium and up to the brain. The bulb receives input from olfactory nerves which constitutes the axons of olfactory receptor neurons. <ref name="PMID12951145 "><pubmed>12951145</pubmed></ref>.

Structures known as glomeruli form by a number of olfactory axons joining together such that each glomerulus obtain information from olfactory neurons which have the identical odour receptors. These glomeruli structures are also surrounded by dendrites belonging to mitral cells which transmit electrical signals to the olfactory cortex in the brain.<ref name="PMID16269360"><pubmed>16269360</pubmed></ref>.

==== Cribiform plate ====

The cribiform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groove allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha. If the cribriform plate happens to get fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose. <ref name="PMID11226964"><pubmed>11226964</pubmed></ref>.

== Normal Function ==

===Olfactory Signal Transduction===

[[File:New olfactory bulb.jpg|450px|thumb|right|Olfactory Bulb]]

Olfactory Signal Transduction is initiated by any substance that emit molecules known as odours. The olfactory transduction is dependent upon the dissolving of these odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors in order for chemical signals to be converted into electrical signals. The transformation into electrical signal is essential for signal transduction for the brain to perceive the initial odourants as smell. <ref name="PMID18066954"><pubmed>18066954</pubmed></ref>.

When odorant molecules bind to receptors in olfactory epithelium, a G protein coupled receptors known as G(αolf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP (cAMP). In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions by binding to and opening cyclic nucleotide gated ion channel to travel through the membrane and enter the cell. <ref name="PMID19652915"><pubmed>19652915</pubmed></ref>. The main effect of ion entry into the cell is depolarisation, and activation of chloride channels resulting in greater depolarisation by the efflux of chloride ions. If the depolarization in the cell is great enough, an action potential is generated on the axon of the receptor cell and transferred to the brain through the olfactory bulb.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

Similar to other G-protein mediated pathways, the olfactory sensory neuron is exposed to negative feedback by the cAMP cascade activated by odours. The negative feedback loop has been discovered to be responsible for the adaption of odours and deactivation of response after exposure for a certain period of time. <ref name="PMID19804753"><pubmed>19804753</pubmed></ref>.

[http://www.youtube.com/watch?v=dIDBG-UPRUI&feature=related| Olfactory Signal Transduction]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

'''Vomeronasal Organ Primordium''': Visible as epithelial swellings on the lower medial aspect of the nasal pit.<ref name="PMID9712194"><pubmed>9712194</pubmed></ref>
The anterior part can be seen as an indentation and the posterior part can be seen as continuous epithelium with the nasal septum. <ref name="PMID11117628"><pubmed>11117628</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.

'''Vomeronasal Organ:''' The VNP's are no longer visible but are instead in the form of bilateral tubes with well delineated lumens, that open anteriorly into the nasal cavity.<ref name="PMID11117628"><pubmed>11117628</pubmed></ref> The VNO epithelium is thicker than respiratory epithelium up until 12 weeks when the respiratory epithelium overtakes in thickness.<ref name="PMID11117628"><pubmed>11117628</pubmed></ref>
The medial sides of the VNO's proliferate into thicker, microvillous sensory epithelium while the the lateral sides are thinner, receptor-free, ciliated epithelium.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

------

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. The following models have been proposed to explain how choanal atresia may occur in the developing human.

<table>
{| width=100%
|-bgcolor="#FF9900 "
| width=20%|'''Risk Factor Model'''
| width=80%|'''Description'''
|-bgcolor="#FFFF99"
| ''' Embryonic'''
| Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence":
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter<ref name="PMID19328897"/>
* Abnormal persistence of mesoderm, resulting in adhesions in the nasochoanal region<ref name="PMID19328897"/>
* Misdirection of neural crest cell migration <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>
|-bgcolor="#FFCC66"
| '''Genetic'''
|
* A study <ref name="PMID3679682"><pubmed> 3679682</pubmed></ref> reported that 30% of children with choanal atresia had '''CHARGE Syndrome''' which stands for: Coloboma, Heart defect, Atresia Choanae, Retarded Growth and development, Genital hypoplasia, Ear anomalies or deafness <ref name="PMID19328897"/>.
* CHD7 gene on chromosome 8q12.1 found in 64% of CHARGE syndrome patients though its function is unknown. <ref name="PMID16155193"><pubmed>16155193</pubmed></ref>
|-bgcolor="#FFFF99"
| '''Molecular'''
|
* '''Thionamides and Hyperthyroidism''': A number of studies reported an increased incidence of choanal atresia in babies of hyperthyroid mothers treated with thionamides<ref name="PMID3688031"><pubmed>3688031</pubmed></ref><ref name="PMID9450891"><pubmed>9450891</pubmed></ref><ref name="PMID18698631"><pubmed>18698631</pubmed></ref>. The majority of hyperthyroid mothers had elevated levels of stimulating antibody for the thyrotropin receptor<ref name="PMID19328897"/>. Human studies and animal models have shown that elevated thyrotropin alters the expression of the growth factor FGF, FGF receptors and angiogenic factors which may play a role in development of choanal atresia<ref name="PMID12746216"><pubmed>18698631</pubmed></ref><ref name="PMID11397875"><pubmed>11397875</pubmed></ref>. However, further research is required in order to determine the exact mechanisms involved.

* '''Retinoic Acid''': Retinoic acid is the product of vitamin A metabolism by retinaldehyde dehydrogenase (Raldh)<ref name="PMID19328897"/>. Mouse models showed that an absence of Raldh causes choanal atresia, resulting in respiratory distress and death of Raldh3 knockout mutants at birth<ref name="PMID14623956"><pubmed>14623956</pubmed></ref>.
|}
</table>

====Clinical Features====

[[File:Choanal atresia computed tomography 01.jpg|300px|thumb|right|Computed Tomography of Choanal Atresia]] Neonates are obligate nose breathers, hence neonatal nasal obstruction as seen in choanal atresia is a serious deformity. In order to avoid severe hypoxia and death, immediate diagnosis and intervention are key<ref name="PMID11232465"><pubmed>11232465<pubmed/></ref>. The severity of the clinical features of choanal atresia depends on the whether the obstruction is unilateral or bilateral <ref name="PMID19328897"/>.

'''Bilateral'''
* At birth present with ''asphyxia neonatorum'': pathological changes caused by hypoxia from affected respiration. A medical emergency requiring an oral airway tube or intubation then immediate surgical intervention<ref name="PMID19328897"/><ref name="PMID12567078"><pubmed>12567078<pubmed/></ref>
* Obvious airway obstruction <ref name="PMID19328897"/>
* Stridor, a harsh vibrating sound when breathing <ref name="PMID19328897"/>
* Paradoxical cyanosis: cyanosis is present in the infant at rest but improves with exertion such as crying <ref name="PMID19328897"/>

'''Unilateral'''
* Not as life threatening as bilateral choanal atresia; more often diagnosed in childhood than in infancy <ref name="PMID19328897"/><ref name="PMID12567078"/>
* Mucoid rhinorrhea, constant mucous fluid discharge from nose <ref name="PMID19328897"/><ref name="PMID12567078"/>
* Dysosmia, distorted olfaction <ref name="PMID12567078"/>
* Obstructive sleep apnea <ref name="PMID12567078"/>

------

===Kallmann's Syndrome===
====Introduction and Epidemiology====
[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|500px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb (OB) is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract. As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

'''Genetic Factors'''
In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:

<table>
{| width=100%
|-bgcolor="#FF9900"
| width=9%|'''Gene'''
| width=20%|'''Mode of Inheritance'''
| width=50%|'''Role in Kallman’s Syndrome'''
|-bgcolor="#FFFF99"
| KAL1
| X-linked
| KAL1 normally encodes glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
|-bgcolor="#FFCC66"
| KAL2 (FGFR1)
| Autosomal-dominant <ref name="PMID20117945"/>
| KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/> <ref name="PMID12627230"><pubmed>12627230</pubmed></ref>. When absent, Kallmann’s syndrome arises due to agenesis or digenesis of the olfactory bulb and failure of GnRH neuronal development and migration.
|-bgcolor="#FFFF99"
| FGF8
| Autosomal-dominant <ref name="PMID20117945"/>
| Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation. Absence produces similar phenotype to KAL2 mutation<ref name="PMID20117945"/>.
|-bgcolor="#FFCC66"
| PROKR2
| Monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID20389090"><pubmed>20389090</pubmed></ref><ref name="PMID18826963"><pubmed>18826963</pubmed></ref>.
| Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"/>.. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>..
|-bgcolor="#FFFF99"
| PROK2
| Hypothesised to have mendelian autosomal recessive transmission in addition to oligogenic transmission<ref name="PMID20389090"/>.
| Encodes the PROKR2 ligand<ref name="PMID18826963"/>. When PROK2 mutated, the ligand is not expressed preventing prokineticin receptor-2 activation; this produces similar effects to PROKR2 abnormalities.

|}
</table>

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell<ref name="PMID22882983"/>. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH<ref name="PMID22882983"/>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* Cryptorchidism: Failure of one or both testes to migrate into the scrotum during male foetus development.
* Gynaecomastia: The development of abnormal mammary glands in males characterised by enlarged breasts.
* Amennorhoea: the absence of menstruation, in females

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification
* Unilateral renal [[#Glossary |'''aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* Pes cavus: Also called clawfoot, refers to a deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. <ref name="PMID16932275"/>
* Neurological symptoms
** Synkinesia: Patients can conduct voluntary movements, however, with accompanied involuntary muscular movements.
** Abnormalities in eye movement
** Cerebellar ataxia: Reduced control over muscle coordination arising from defects or damage to the cerebellum.
** Evoked horizontal nystagmus: fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.
** Sensorineural deafness
** Spatial attentional abnormalities
** Spastic paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>

===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
[http://www.ncbi.nlm.nih.gov/pubmed/21543621 Forni PE et al.]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]][http://www.ncbi.nlm.nih.gov/pubmed/21943152 ''The dual origin of the peripheral olfactory system''] also investigated the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
[http://www.ncbi.nlm.nih.gov/pubmed/22906231 Shaker T. et al.] published a paper in August this year looking into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular section of the research looked to determine whether Neurog1 and Neurog2 were required for olfactory bulb development. A loss-of-function technique was utilised to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
[[File:Absence_of_CSFR1_Impacts_Normal_Development_of_Brain_Architecture.jpg|200px|thumb|left|'''Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development'''- Absence of CSF-1R results in perturbed brain architecture.]]A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Ectoderm:''' The outermost layer of the trilaminar embryo. Differentiates to form structures including the epidermis and neural tissue.

'''Epiblast:''' The collective term for embryonic mesoderm and ectoderm before differentiation

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

[http://kallmanns.org/ The Kallmann's Syndrome Organisation]

==Additional images==
<gallery>
Image:Vomeronasal_Organ_position.jpg
Image:Nasal_placode_diagram.jpeg
Image:Olfactory_bulb_and_epithelium.png
Image:Olfactory_epithelium.jpg
Image:New_olfactory_bulb.jpg
Image:Choanal_atresia_computed_tomography_01.jpg
Image:Normal_Neuronal_Migration_into_the_Olfactory_Bulb_Compared_to_Kallmann's_Syndrome.jpg
Image:Neural_crest-derived_cells_in_the_embryonic_olfactory_epithelium.jpg
Image:Absence_of_CSFR1_Impacts_Normal_Development_of_Brain_Architecture.jpg
</gallery>

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-10-02T05:07:51Z

Z3374215: /* Pathophysiology */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
|[[File:Vomeronasal Organ position.jpg|thumb|right|200px|alt=Alt|''Vomeronasal Organ position''']]

Discovery of [[#Glossary|'''Vomeronasal organ''']] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|'''hypogonadism''']] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|'''epiblast''']], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of [[#Glossary|'''ectoderm''']]<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|'''cribriform plate''']]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia and midline anatomic defects) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for revealing the large number of genes involved in odour reception. <ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|350px|right|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]
[http://www.example.com Nasal Cavity]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells. <ref name="PMID7143026"><pubmed>7143026</pubmed></ref>.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.<ref name="PMID17468753 "><pubmed>17468753 </pubmed></ref>.

[http://www.ncbi.nlm.nih.gov/books/NBK10896/ Olfactory epithelium]
==== Olfactory Bulb ====

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined. The olfactory bulb is essential for olfaction as it transmits information from the olfactory epithelium and up to the brain. The bulb receives input from olfactory nerves which constitutes the axons of olfactory receptor neurons. <ref name="PMID12951145 "><pubmed>12951145</pubmed></ref>.

Structures known as glomeruli form by a number of olfactory axons joining together such that each glomerulus obtain information from olfactory neurons which have the identical odour receptors. These glomeruli structures are also surrounded by dendrites belonging to mitral cells which transmit electrical signals to the olfactory cortex in the brain.<ref name="PMID16269360"><pubmed>16269360</pubmed></ref>.

==== Cribiform plate ====

The cribiform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groove allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha. If the cribriform plate happens to get fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose. <ref name="PMID11226964"><pubmed>11226964</pubmed></ref>.

== Normal Function ==

===Olfactory Signal Transduction===

[[File:New olfactory bulb.jpg|450px|thumb|right|Olfactory Bulb]]

Olfactory Signal Transduction is initiated by any substance that emit molecules known as odours. The olfactory transduction is dependent upon the dissolving of these odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors in order for chemical signals to be converted into electrical signals. The transformation into electrical signal is essential for signal transduction for the brain to perceive the initial odourants as smell. <ref name="PMID18066954"><pubmed>18066954</pubmed></ref>.

When odorant molecules bind to receptors in olfactory epithelium, a G protein coupled receptors known as G(αolf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP (cAMP). In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions by binding to and opening cyclic nucleotide gated ion channel to travel through the membrane and enter the cell. <ref name="PMID19652915"><pubmed>19652915</pubmed></ref>. The main effect of ion entry into the cell is depolarisation, and activation of chloride channels resulting in greater depolarisation by the efflux of chloride ions. If the depolarization in the cell is great enough, an action potential is generated on the axon of the receptor cell and transferred to the brain through the olfactory bulb.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

Similar to other G-protein mediated pathways, the olfactory sensory neuron is exposed to negative feedback by the cAMP cascade activated by odours. The negative feedback loop has been discovered to be responsible for the adaption of odours and deactivation of response after exposure for a certain period of time. <ref name="PMID19804753"><pubmed>19804753</pubmed></ref>.

[http://www.youtube.com/watch?v=dIDBG-UPRUI&feature=related| Olfactory Signal Transduction]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

------

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. The following models have been proposed to explain how choanal atresia may occur in the developing human.

<table>
{| width=100%
|-bgcolor="FF9900 "
| width=20%|'''Risk Factor Model'''
| width=80%|'''Description'''
|-bgcolor="FFFF99"
| ''' Embryonic'''
| Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence":
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter<ref name="PMID19328897"/>
* Abnormal persistence of mesoderm, resulting in adhesions in the nasochoanal region<ref name="PMID19328897"/>
* Misdirection of neural crest cell migration <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>
|-bgcolor="FFCC66"
| '''Genetic'''
|
* A study <ref name="PMID3679682"><pubmed> 3679682</pubmed></ref> reported that 30% of children with choanal atresia had '''CHARGE Syndrome''' which stands for: Coloboma, Heart defect, Atresia Choanae, Retarded Growth and development, Genital hypoplasia, Ear anomalies or deafness <ref name="PMID19328897"/>.
* CHD7 gene on chromosome 8q12.1 found in 64% of CHARGE syndrome patients though its function is unknown. <ref name="PMID16155193"><pubmed>16155193</pubmed></ref>
|-bgcolor="FFFF99"
| '''Molecular'''
|
* '''Thionamides and Hyperthyroidism''': A number of studies reported an increased incidence of choanal atresia in babies of hyperthyroid mothers treated with thionamides<ref name="PMID3688031"><pubmed>3688031</pubmed></ref><ref name="PMID9450891"><pubmed>9450891</pubmed></ref><ref name="PMID18698631"><pubmed>18698631</pubmed></ref>. The majority of hyperthyroid mothers had elevated levels of stimulating antibody for the thyrotropin receptor<ref name="PMID19328897"/>. Human studies and animal models have shown that elevated thyrotropin alters the expression of the growth factor FGF, FGF receptors and angiogenic factors which may play a role in development of choanal atresia<ref name="PMID12746216"><pubmed>18698631</pubmed></ref><ref name="PMID11397875"><pubmed>11397875</pubmed></ref>. However, further research is required in order to determine the exact mechanisms involved.

* '''Retinoic Acid''': Retinoic acid is the product of vitamin A metabolism by retinaldehyde dehydrogenase (Raldh)<ref name="PMID19328897"/>. Mouse models showed that an absence of Raldh causes choanal atresia, resulting in respiratory distress and death of Raldh3 knockout mutants at birth<ref name="PMID14623956"><pubmed>14623956</pubmed></ref>.
|}
</table>

====Clinical Features====

[[File:Choanal atresia computed tomography 01.jpg|300px|thumb|right|Computed Tomography of Choanal Atresia]] Neonates are obligate nose breathers, hence neonatal nasal obstruction as seen in choanal atresia is a serious deformity. In order to avoid severe hypoxia and death, immediate diagnosis and intervention are key<ref name="PMID11232465"><pubmed>11232465<pubmed/></ref>. The severity of the clinical features of choanal atresia depends on the whether the obstruction is unilateral or bilateral <ref name="PMID19328897"/>.

'''Bilateral'''
* At birth present with ''asphyxia neonatorum'': pathological changes caused by hypoxia from affected respiration. A medical emergency requiring an oral airway tube or intubation then immediate surgical intervention<ref name="PMID19328897"/><ref name="PMID12567078"><pubmed>12567078<pubmed/></ref>
* Obvious airway obstruction <ref name="PMID19328897"/>
* Stridor, a harsh vibrating sound when breathing <ref name="PMID19328897"/>
* Paradoxical cyanosis: cyanosis is present in the infant at rest but improves with exertion such as crying <ref name="PMID19328897"/>

'''Unilateral'''
* Not as life threatening as bilateral choanal atresia; more often diagnosed in childhood than in infancy <ref name="PMID19328897"/><ref name="PMID12567078"/>
* Mucoid rhinorrhea, constant mucous fluid discharge from nose <ref name="PMID19328897"/><ref name="PMID12567078"/>
* Dysosmia, distorted olfaction <ref name="PMID12567078"/>
* Obstructive sleep apnea <ref name="PMID12567078"/>

------

===Kallmann's Syndrome===
====Introduction and Epidemiology====
[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|500px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb (OB) is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract. As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

'''Genetic Factors'''
In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:

<table>
{| width=100%
|-bgcolor="#FF9900"
| width=9%|'''Gene'''
| width=20%|'''Mode of Inheritance'''
| width=50%|'''Role in Kallman’s Syndrome'''
|-bgcolor="#FFFF99"
| KAL1
| X-linked
| KAL1 normally encodes glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
|-bgcolor="#FFCC66"
| KAL2 (FGFR1)
| Autosomal-dominant <ref name="PMID20117945"/>
| KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/> <ref name="PMID12627230"><pubmed>12627230</pubmed></ref>. When absent, Kallmann’s syndrome arises due to agenesis or digenesis of the olfactory bulb and failure of GnRH neuronal development and migration.
|-bgcolor="#FFFF99"
| FGF8
| Autosomal-dominant <ref name="PMID20117945"/>
| Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation. Absence produces similar phenotype to KAL2 mutation<ref name="PMID20117945"/>.
|-bgcolor="#FFCC66"
| PROKR2
| Monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID20389090"><pubmed>20389090</pubmed></ref><ref name="PMID18826963"><pubmed>18826963</pubmed></ref>.
| Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"/>.. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>..
|-bgcolor="#FFFF99"
| PROK2
| Hypothesised to have mendelian autosomal recessive transmission in addition to oligogenic transmission<ref name="PMID20389090"/>.
| Encodes the PROKR2 ligand<ref name="PMID18826963"/>. When PROK2 mutated, the ligand is not expressed preventing prokineticin receptor-2 activation; this produces similar effects to PROKR2 abnormalities.

|}
</table>

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell<ref name="PMID22882983"/>. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH<ref name="PMID22882983"/>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* Cryptorchidism: Failure of one or both testes to migrate into the scrotum during male foetus development.
* Gynaecomastia: The development of abnormal mammary glands in males characterised by enlarged breasts.
* Amennorhoea: the absence of menstruation, in females

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification
* Unilateral renal [[#Glossary |'''aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* Pes cavus: Also called clawfoot, refers to a deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. <ref name="PMID16932275"/>
* Neurological symptoms
** Synkinesia: Patients can conduct voluntary movements, however, with accompanied involuntary muscular movements.
** Abnormalities in eye movement
** Cerebellar ataxia: Reduced control over muscle coordination arising from defects or damage to the cerebellum.
** Evoked horizontal nystagmus: fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.
** Sensorineural deafness
** Spatial attentional abnormalities
** Spastic paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>

===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
[http://www.ncbi.nlm.nih.gov/pubmed/21543621 Forni PE et al.]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]][http://www.ncbi.nlm.nih.gov/pubmed/21943152 ''The dual origin of the peripheral olfactory system''] also investigated the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
[http://www.ncbi.nlm.nih.gov/pubmed/22906231 Shaker T. et al.] published a paper in August this year looking into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular section of the research looked to determine whether Neurog1 and Neurog2 were required for olfactory bulb development. A loss-of-function technique was utilised to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
[[File:Absence_of_CSFR1_Impacts_Normal_Development_of_Brain_Architecture.jpg|200px|thumb|left|'''Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development'''- Absence of CSF-1R results in perturbed brain architecture.]]A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Ectoderm:''' The outermost layer of the trilaminar embryo. Differentiates to form structures including the epidermis and neural tissue.

'''Epiblast:''' The collective term for embryonic mesoderm and ectoderm before differentiation

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

[http://kallmanns.org/ The Kallmann's Syndrome Organisation]

==Additional images==
<gallery>
Image:Vomeronasal_Organ_position.jpg
Image:Nasal_placode_diagram.jpeg
Image:Olfactory_bulb_and_epithelium.png
Image:Olfactory_epithelium.jpg
Image:New_olfactory_bulb.jpg
Image:Choanal_atresia_computed_tomography_01.jpg
Image:Normal_Neuronal_Migration_into_the_Olfactory_Bulb_Compared_to_Kallmann's_Syndrome.jpg
Image:Neural_crest-derived_cells_in_the_embryonic_olfactory_epithelium.jpg
Image:Absence_of_CSFR1_Impacts_Normal_Development_of_Brain_Architecture.jpg
</gallery>

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-10-01T03:56:09Z

Z3374215: /* History of Discovery */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
|[[File:Vomeronasal Organ position.jpg|thumb|right|200px|alt=Alt|''Vomeronasal Organ position''']]

Discovery of [[#Glossary|'''Vomeronasal organ''']] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|'''hypogonadism''']] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|'''epiblast''']], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of [[#Glossary|'''ectoderm''']]<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|'''cribriform plate''']]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia and midline anatomic defects) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for revealing the large number of genes involved in odour reception. <ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribriform plate ====

The cribriform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribriform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

[http://www.youtube.com/watch?v=ABw68BsCMCs| http://www.youtube.com/watch?v=fIFWt6WWYO0&feature=related]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* Cryptorchidism: Failure of one or both testes to migrate into the scrotum during male foetus development.
* Gynaecomastia: The development of abnormal mammary glands in males characterised by enlarged breasts.
* Amennorhoea: the absence of menstruation, in females

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* Unilateral renal [[#Glossary |'''aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* Pes cavus: Also called clawfoot, refers to a deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. <ref name="PMID16932275"/>
* Neurological symptoms
** Synkinesia: Patients can conduct voluntary movements, however, with accompanied involuntary muscular movements.
** Abnormalities in eye movement
** Cerebellar ataxia: Reduced control over muscle coordination arising from defects or damage to the cerebellum.
** Evoked horizontal nystagmus: fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.
** Sensorineural deafness
** Spatial attentional abnormalities
** Spastic paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>

===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
[http://www.ncbi.nlm.nih.gov/pubmed/21543621 Forni PE et al.]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]][http://www.ncbi.nlm.nih.gov/pubmed/21943152 ''The dual origin of the peripheral olfactory system''] also investigated the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
[http://www.ncbi.nlm.nih.gov/pubmed/22906231 Shaker T. et al.] published a paper in August this year looking into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular section of the research looked to determine whether Neurog1 and Neurog2 were required for olfactory bulb development. A loss-of-function technique was utilised to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Ectoderm:''' The outermost layer of the trilaminar embryo. Differentiates to form structures including the epidermis and neural tissue.

'''Epiblast:''' The collective term for embryonic mesoderm and ectoderm before differentiation

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-10-01T03:55:34Z

Z3374215: /* History of Discovery */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
|[[File:Vomeronasal Organ position.jpg|thumb|right|200px|alt=Alt|''Vomeronasal Organ position''']]

Discovery of [[#Glossary|'''Vomeronasal organ''']] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|'''hypogonadism''']] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|'''epiblast''']], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of [[#Glossary|'''ectoderm''']]<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|'''cribriform plate''']]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia and midline anatomic defects) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for revealing the large number of genes involved in odour reception. <ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribriform plate ====

The cribriform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribriform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

[http://www.youtube.com/watch?v=ABw68BsCMCs| http://www.youtube.com/watch?v=fIFWt6WWYO0&feature=related]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* Cryptorchidism: Failure of one or both testes to migrate into the scrotum during male foetus development.
* Gynaecomastia: The development of abnormal mammary glands in males characterised by enlarged breasts.
* Amennorhoea: the absence of menstruation, in females

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* Unilateral renal [[#Glossary |'''aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* Pes cavus: Also called clawfoot, refers to a deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. <ref name="PMID16932275"/>
* Neurological symptoms
** Synkinesia: Patients can conduct voluntary movements, however, with accompanied involuntary muscular movements.
** Abnormalities in eye movement
** Cerebellar ataxia: Reduced control over muscle coordination arising from defects or damage to the cerebellum.
** Evoked horizontal nystagmus: fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.
** Sensorineural deafness
** Spatial attentional abnormalities
** Spastic paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>

===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
[http://www.ncbi.nlm.nih.gov/pubmed/21543621 Forni PE et al.]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]][http://www.ncbi.nlm.nih.gov/pubmed/21943152 ''The dual origin of the peripheral olfactory system''] also investigated the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
[http://www.ncbi.nlm.nih.gov/pubmed/22906231 Shaker T. et al.] published a paper in August this year looking into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular section of the research looked to determine whether Neurog1 and Neurog2 were required for olfactory bulb development. A loss-of-function technique was utilised to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Ectoderm:''' The outermost layer of the trilaminar embryo. Differentiates to form structures including the epidermis and neural tissue.

'''Epiblast:''' The collective term for embryonic mesoderm and ectoderm before differentiation

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

File:Vomeronasal Organ position.jpg

2012-10-01T03:54:54Z

Z3374215:

Student drawn image

This image demonstrates the position of the vomeronasal organ in relation to the olfactory bulb and tract.
{{Template:Student Image}}

2012 Group Project 4

2012-10-01T03:54:27Z

Z3374215: /* History of Discovery */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
|[[File:Vomeronasal Organ position.jpg|thumb|right|200px|alt=Alt|''Vomeronasal Organ position''']]

Discovery of [[#Glossary|'''Vomeronasal organ''']] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|'''hypogonadism''']] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|'''epiblast''']], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of [[#Glossary|'''ectoderm''']]<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|'''cribriform plate''']]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia and midline anatomic defects) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for revealing the large number of genes involved in odour reception. <ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribriform plate ====

The cribriform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribriform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

[http://www.youtube.com/watch?v=ABw68BsCMCs| http://www.youtube.com/watch?v=fIFWt6WWYO0&feature=related]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* Cryptorchidism: Failure of one or both testes to migrate into the scrotum during male foetus development.
* Gynaecomastia: The development of abnormal mammary glands in males characterised by enlarged breasts.
* Amennorhoea: the absence of menstruation, in females

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* Unilateral renal [[#Glossary |'''aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* Pes cavus: Also called clawfoot, refers to a deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. <ref name="PMID16932275"/>
* Neurological symptoms
** Synkinesia: Patients can conduct voluntary movements, however, with accompanied involuntary muscular movements.
** Abnormalities in eye movement
** Cerebellar ataxia: Reduced control over muscle coordination arising from defects or damage to the cerebellum.
** Evoked horizontal nystagmus: fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.
** Sensorineural deafness
** Spatial attentional abnormalities
** Spastic paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>

===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
[http://www.ncbi.nlm.nih.gov/pubmed/21543621 Forni PE et al.]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]][http://www.ncbi.nlm.nih.gov/pubmed/21943152 ''The dual origin of the peripheral olfactory system''] also investigated the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
[http://www.ncbi.nlm.nih.gov/pubmed/22906231 Shaker T. et al.] published a paper in August this year looking into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular section of the research looked to determine whether Neurog1 and Neurog2 were required for olfactory bulb development. A loss-of-function technique was utilised to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Ectoderm:''' The outermost layer of the trilaminar embryo. Differentiates to form structures including the epidermis and neural tissue.

'''Epiblast:''' The collective term for embryonic mesoderm and ectoderm before differentiation

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-10-01T03:53:48Z

Z3374215: /* History of Discovery */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
|[[File:Vomeronasal Organ position.jpg|thumb|left|250px|alt=Alt|''Vomeronasal Organ position''']]

Discovery of [[#Glossary|'''Vomeronasal organ''']] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|'''hypogonadism''']] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|'''epiblast''']], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of [[#Glossary|'''ectoderm''']]<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|'''cribriform plate''']]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia and midline anatomic defects) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for revealing the large number of genes involved in odour reception. <ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribriform plate ====

The cribriform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribriform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

[http://www.youtube.com/watch?v=ABw68BsCMCs| http://www.youtube.com/watch?v=fIFWt6WWYO0&feature=related]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* Cryptorchidism: Failure of one or both testes to migrate into the scrotum during male foetus development.
* Gynaecomastia: The development of abnormal mammary glands in males characterised by enlarged breasts.
* Amennorhoea: the absence of menstruation, in females

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* Unilateral renal [[#Glossary |'''aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* Pes cavus: Also called clawfoot, refers to a deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. <ref name="PMID16932275"/>
* Neurological symptoms
** Synkinesia: Patients can conduct voluntary movements, however, with accompanied involuntary muscular movements.
** Abnormalities in eye movement
** Cerebellar ataxia: Reduced control over muscle coordination arising from defects or damage to the cerebellum.
** Evoked horizontal nystagmus: fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.
** Sensorineural deafness
** Spatial attentional abnormalities
** Spastic paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>

===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
[http://www.ncbi.nlm.nih.gov/pubmed/21543621 Forni PE et al.]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]][http://www.ncbi.nlm.nih.gov/pubmed/21943152 ''The dual origin of the peripheral olfactory system''] also investigated the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
[http://www.ncbi.nlm.nih.gov/pubmed/22906231 Shaker T. et al.] published a paper in August this year looking into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular section of the research looked to determine whether Neurog1 and Neurog2 were required for olfactory bulb development. A loss-of-function technique was utilised to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Ectoderm:''' The outermost layer of the trilaminar embryo. Differentiates to form structures including the epidermis and neural tissue.

'''Epiblast:''' The collective term for embryonic mesoderm and ectoderm before differentiation

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-10-01T03:52:27Z

Z3374215: /* History of Discovery */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
|[[File:Vomeronasal Organ position.jpg|thumb|right|250px|alt=Alt|''Vomeronasal Organ position''']]

Discovery of [[#Glossary|'''Vomeronasal organ''']] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|'''hypogonadism''']] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|'''epiblast''']], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of [[#Glossary|'''ectoderm''']]<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|'''cribriform plate''']]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia and midline anatomic defects) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for revealing the large number of genes involved in odour reception. <ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribriform plate ====

The cribriform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribriform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

[http://www.youtube.com/watch?v=ABw68BsCMCs| http://www.youtube.com/watch?v=fIFWt6WWYO0&feature=related]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* Cryptorchidism: Failure of one or both testes to migrate into the scrotum during male foetus development.
* Gynaecomastia: The development of abnormal mammary glands in males characterised by enlarged breasts.
* Amennorhoea: the absence of menstruation, in females

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* Unilateral renal [[#Glossary |'''aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* Pes cavus: Also called clawfoot, refers to a deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. <ref name="PMID16932275"/>
* Neurological symptoms
** Synkinesia: Patients can conduct voluntary movements, however, with accompanied involuntary muscular movements.
** Abnormalities in eye movement
** Cerebellar ataxia: Reduced control over muscle coordination arising from defects or damage to the cerebellum.
** Evoked horizontal nystagmus: fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.
** Sensorineural deafness
** Spatial attentional abnormalities
** Spastic paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>

===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
[http://www.ncbi.nlm.nih.gov/pubmed/21543621 Forni PE et al.]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]][http://www.ncbi.nlm.nih.gov/pubmed/21943152 ''The dual origin of the peripheral olfactory system''] also investigated the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
[http://www.ncbi.nlm.nih.gov/pubmed/22906231 Shaker T. et al.] published a paper in August this year looking into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular section of the research looked to determine whether Neurog1 and Neurog2 were required for olfactory bulb development. A loss-of-function technique was utilised to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Ectoderm:''' The outermost layer of the trilaminar embryo. Differentiates to form structures including the epidermis and neural tissue.

'''Epiblast:''' The collective term for embryonic mesoderm and ectoderm before differentiation

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

File:Vomeronasal Organ position.jpg

2012-10-01T03:50:04Z

Z3374215: Student drawn image This image demonstrates the position of the vomeronasal organ in relation to the olfactory bulb and tract. {{Template:Student Image}}

Student drawn image
This image demonstrates the position of the vomeronasal organ in relation to the olfactory bulb and tract.
{{Template:Student Image}}

2012 Group Project 4

2012-10-01T03:44:24Z

Z3374215: /* History of Discovery */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
| Discovery of [[#Glossary|'''Vomeronasal organ''']] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|'''hypogonadism''']] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|'''epiblast''']], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of [[#Glossary|'''ectoderm''']]<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|'''cribriform plate''']]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia and midline anatomic defects) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for revealing the large number of genes involved in odour reception. <ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribriform plate ====

The cribriform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribriform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

[http://www.youtube.com/watch?v=ABw68BsCMCs| http://www.youtube.com/watch?v=fIFWt6WWYO0&feature=related]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* Cryptorchidism: Failure of one or both testes to migrate into the scrotum during male foetus development.
* Gynaecomastia: The development of abnormal mammary glands in males characterised by enlarged breasts.
* Amennorhoea: the absence of menstruation, in females

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* Unilateral renal [[#Glossary |'''aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* Pes cavus: Also called clawfoot, refers to a deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. <ref name="PMID16932275"/>
* Neurological symptoms
** Synkinesia: Patients can conduct voluntary movements, however, with accompanied involuntary muscular movements.
** Abnormalities in eye movement
** Cerebellar ataxia: Reduced control over muscle coordination arising from defects or damage to the cerebellum.
** Evoked horizontal nystagmus: fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.
** Sensorineural deafness
** Spatial attentional abnormalities
** Spastic paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>

===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
[http://www.ncbi.nlm.nih.gov/pubmed/21543621 Forni PE et al.]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]][http://www.ncbi.nlm.nih.gov/pubmed/21943152 ''The dual origin of the peripheral olfactory system''] also investigated the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
[http://www.ncbi.nlm.nih.gov/pubmed/22906231 Shaker T. et al.] published a paper in August this year looking into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular section of the research looked to determine whether Neurog1 and Neurog2 were required for olfactory bulb development. A loss-of-function technique was utilised to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Ectoderm:''' The outermost layer of the trilaminar embryo. Differentiates to form structures including the epidermis and neural tissue.

'''Epiblast:''' The collective term for embryonic mesoderm and ectoderm before differentiation

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-10-01T02:57:09Z

Z3374215: /* History of Discovery */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
| Discovery of [[#Glossary|Vomeronasal organ]] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|hypogonadism]] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|epiblast]], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of [[#Glossary|ectoderm]]<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|cribriform plate]]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|Kallmann's Syndrome]]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia, midline anatomic defect) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for revealing the large number of genes involved in odour reception. <ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribriform plate ====

The cribriform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribriform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

[http://www.youtube.com/watch?v=ABw68BsCMCs| http://www.youtube.com/watch?v=fIFWt6WWYO0&feature=related]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* [[#Glossary |'''Cryptorchidism''']] (males)
* [[#Glossary |'''Gynaecomastia''']] (males)
* Absence of menstruation, amennorhoea (femaleS)

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* [[#Glossary |'''Unilateral renal aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* [[#Glossary |'''Pes cavus''']] <ref name="PMID16932275"/>
* Neurological symptoms
** [[#Glossary |'''Synkinesia''']]
** Abnormalities in eye movement
** [[#Glossary |'''Cerebellar ataxia''']]
** Evoked horizontal [[#Glossary |'''nystagmus''']]
** Sensorineural deafness
** Spatial attentional abnormalities
** [[#Glossary |'''Spastic paraplegia''']]
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>
===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
[http://www.ncbi.nlm.nih.gov/pubmed/21543621 Forni PE et al.]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]][http://www.ncbi.nlm.nih.gov/pubmed/21943152 ''The dual origin of the peripheral olfactory system''] also investigated the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
[http://www.ncbi.nlm.nih.gov/pubmed/22906231 Shaker T. et al.] published a paper in August this year looking into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular section of the research looked to determine whether Neurog1 and Neurog2 were required for olfactory bulb development. A loss-of-function technique was utilised to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cryptorchidism:''' Failure of one or both testes to migrate into the scrotum during male foetus development.

'''Ectoderm:''' The outermost layer of the trilaminar embryo. Differentiates to form structures including the epidermis and neural tissue.

'''Epiblast:''' The collective term for embryonic mesoderm and ectoderm before differentiation

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Gynaecomastia:''' The development of abnormal mammary glands in males characterised by enlarged breasts.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nystagmus:''' Refers to fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Pes cavus:''' A deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. Also referred to as clawfoot.

'''Spastic paraplegia:''' A hereditary paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.

'''Synkinesia:''' Refers to the ability to conduct voluntary movements, however, with accompanied involuntary muscular movements.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-10-01T02:40:17Z

Z3374215: /* Contribution of Neural Crest and Ectoderm to Nasal Placode */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
| Discovery of [[#Glossary|Vomeronasal organ]] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|hypogonadism]] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|epiblast]], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of [[#Glossary|ectoderm]]<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|cribriform plate]]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|Kallmann's Syndrome]]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia, midline anatomic defect) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for their work on the olfactory system<ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribriform plate ====

The cribriform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribriform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

[http://www.youtube.com/watch?v=ABw68BsCMCs| http://www.youtube.com/watch?v=fIFWt6WWYO0&feature=related]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* [[#Glossary |'''Cryptorchidism''']] (males)
* [[#Glossary |'''Gynaecomastia''']] (males)
* Absence of menstruation, amennorhoea (femaleS)

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* [[#Glossary |'''Unilateral renal aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* [[#Glossary |'''Pes cavus''']] <ref name="PMID16932275"/>
* Neurological symptoms
** [[#Glossary |'''Synkinesia''']]
** Abnormalities in eye movement
** [[#Glossary |'''Cerebellar ataxia''']]
** Evoked horizontal [[#Glossary |'''nystagmus''']]
** Sensorineural deafness
** Spatial attentional abnormalities
** [[#Glossary |'''Spastic paraplegia''']]
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>
===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
[http://www.ncbi.nlm.nih.gov/pubmed/21543621 Forni PE et al.]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]][http://www.ncbi.nlm.nih.gov/pubmed/21943152 ''The dual origin of the peripheral olfactory system''] also investigated the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
[http://www.ncbi.nlm.nih.gov/pubmed/22906231 Shaker T. et al.] published a paper in August this year looking into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular section of the research looked to determine whether Neurog1 and Neurog2 were required for olfactory bulb development. A loss-of-function technique was utilised to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cryptorchidism:''' Failure of one or both testes to migrate into the scrotum during male foetus development.

'''Ectoderm:''' The outermost layer of the trilaminar embryo. Differentiates to form structures including the epidermis and neural tissue.

'''Epiblast:''' The collective term for embryonic mesoderm and ectoderm before differentiation

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Gynaecomastia:''' The development of abnormal mammary glands in males characterised by enlarged breasts.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nystagmus:''' Refers to fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Pes cavus:''' A deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. Also referred to as clawfoot.

'''Spastic paraplegia:''' A hereditary paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.

'''Synkinesia:''' Refers to the ability to conduct voluntary movements, however, with accompanied involuntary muscular movements.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-10-01T02:39:33Z

Z3374215: /* Contribution of Neural Crest and Ectoderm to Nasal Placode */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
| Discovery of [[#Glossary|Vomeronasal organ]] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|hypogonadism]] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|epiblast]], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of [[#Glossary|ectoderm]]<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|cribriform plate]]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|Kallmann's Syndrome]]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia, midline anatomic defect) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for their work on the olfactory system<ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribriform plate ====

The cribriform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribriform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

[http://www.youtube.com/watch?v=ABw68BsCMCs| http://www.youtube.com/watch?v=fIFWt6WWYO0&feature=related]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* [[#Glossary |'''Cryptorchidism''']] (males)
* [[#Glossary |'''Gynaecomastia''']] (males)
* Absence of menstruation, amennorhoea (femaleS)

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* [[#Glossary |'''Unilateral renal aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* [[#Glossary |'''Pes cavus''']] <ref name="PMID16932275"/>
* Neurological symptoms
** [[#Glossary |'''Synkinesia''']]
** Abnormalities in eye movement
** [[#Glossary |'''Cerebellar ataxia''']]
** Evoked horizontal [[#Glossary |'''nystagmus''']]
** Sensorineural deafness
** Spatial attentional abnormalities
** [[#Glossary |'''Spastic paraplegia''']]
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>
===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
A [http://www.ncbi.nlm.nih.gov/pubmed/21543621 Forni PE et al.]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]][http://www.ncbi.nlm.nih.gov/pubmed/21943152 ''The dual origin of the peripheral olfactory system''] also investigated the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
[http://www.ncbi.nlm.nih.gov/pubmed/22906231 Shaker T. et al.] published a paper in August this year looking into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular section of the research looked to determine whether Neurog1 and Neurog2 were required for olfactory bulb development. A loss-of-function technique was utilised to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cryptorchidism:''' Failure of one or both testes to migrate into the scrotum during male foetus development.

'''Ectoderm:''' The outermost layer of the trilaminar embryo. Differentiates to form structures including the epidermis and neural tissue.

'''Epiblast:''' The collective term for embryonic mesoderm and ectoderm before differentiation

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Gynaecomastia:''' The development of abnormal mammary glands in males characterised by enlarged breasts.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nystagmus:''' Refers to fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Pes cavus:''' A deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. Also referred to as clawfoot.

'''Spastic paraplegia:''' A hereditary paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.

'''Synkinesia:''' Refers to the ability to conduct voluntary movements, however, with accompanied involuntary muscular movements.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-10-01T02:37:14Z

Z3374215: /* Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
| Discovery of [[#Glossary|Vomeronasal organ]] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|hypogonadism]] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|epiblast]], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of [[#Glossary|ectoderm]]<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|cribriform plate]]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|Kallmann's Syndrome]]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia, midline anatomic defect) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for their work on the olfactory system<ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribriform plate ====

The cribriform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribriform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

[http://www.youtube.com/watch?v=ABw68BsCMCs| http://www.youtube.com/watch?v=fIFWt6WWYO0&feature=related]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* [[#Glossary |'''Cryptorchidism''']] (males)
* [[#Glossary |'''Gynaecomastia''']] (males)
* Absence of menstruation, amennorhoea (femaleS)

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* [[#Glossary |'''Unilateral renal aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* [[#Glossary |'''Pes cavus''']] <ref name="PMID16932275"/>
* Neurological symptoms
** [[#Glossary |'''Synkinesia''']]
** Abnormalities in eye movement
** [[#Glossary |'''Cerebellar ataxia''']]
** Evoked horizontal [[#Glossary |'''nystagmus''']]
** Sensorineural deafness
** Spatial attentional abnormalities
** [[#Glossary |'''Spastic paraplegia''']]
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>
===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
A [http://www.ncbi.nlm.nih.gov/pubmed/21543621 paper]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]][http://www.ncbi.nlm.nih.gov/pubmed/21943152 ''The dual origin of the peripheral olfactory system''] also investigated the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
[http://www.ncbi.nlm.nih.gov/pubmed/22906231 Shaker T. et al.] published a paper in August this year looking into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular section of the research looked to determine whether Neurog1 and Neurog2 were required for olfactory bulb development. A loss-of-function technique was utilised to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cryptorchidism:''' Failure of one or both testes to migrate into the scrotum during male foetus development.

'''Ectoderm:''' The outermost layer of the trilaminar embryo. Differentiates to form structures including the epidermis and neural tissue.

'''Epiblast:''' The collective term for embryonic mesoderm and ectoderm before differentiation

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Gynaecomastia:''' The development of abnormal mammary glands in males characterised by enlarged breasts.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nystagmus:''' Refers to fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Pes cavus:''' A deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. Also referred to as clawfoot.

'''Spastic paraplegia:''' A hereditary paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.

'''Synkinesia:''' Refers to the ability to conduct voluntary movements, however, with accompanied involuntary muscular movements.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-10-01T02:34:14Z

Z3374215: /* Contribution of Cranial Neural Crest to Olfactory System */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
| Discovery of [[#Glossary|Vomeronasal organ]] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|hypogonadism]] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|epiblast]], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of [[#Glossary|ectoderm]]<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|cribriform plate]]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|Kallmann's Syndrome]]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia, midline anatomic defect) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for their work on the olfactory system<ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribriform plate ====

The cribriform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribriform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

[http://www.youtube.com/watch?v=ABw68BsCMCs| http://www.youtube.com/watch?v=fIFWt6WWYO0&feature=related]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* [[#Glossary |'''Cryptorchidism''']] (males)
* [[#Glossary |'''Gynaecomastia''']] (males)
* Absence of menstruation, amennorhoea (femaleS)

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* [[#Glossary |'''Unilateral renal aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* [[#Glossary |'''Pes cavus''']] <ref name="PMID16932275"/>
* Neurological symptoms
** [[#Glossary |'''Synkinesia''']]
** Abnormalities in eye movement
** [[#Glossary |'''Cerebellar ataxia''']]
** Evoked horizontal [[#Glossary |'''nystagmus''']]
** Sensorineural deafness
** Spatial attentional abnormalities
** [[#Glossary |'''Spastic paraplegia''']]
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>
===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
A [http://www.ncbi.nlm.nih.gov/pubmed/21543621 paper]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]][http://www.ncbi.nlm.nih.gov/pubmed/21943152 ''The dual origin of the peripheral olfactory system''] also investigated the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
A [http://www.ncbi.nlm.nih.gov/pubmed/22906231 study] from August this year looked into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular part of the research looking to determine whether Neurog1 and Neurog2 were required for olfactory bulb development utilised a loss-of-function technique to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cryptorchidism:''' Failure of one or both testes to migrate into the scrotum during male foetus development.

'''Ectoderm:''' The outermost layer of the trilaminar embryo. Differentiates to form structures including the epidermis and neural tissue.

'''Epiblast:''' The collective term for embryonic mesoderm and ectoderm before differentiation

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Gynaecomastia:''' The development of abnormal mammary glands in males characterised by enlarged breasts.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nystagmus:''' Refers to fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Pes cavus:''' A deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. Also referred to as clawfoot.

'''Spastic paraplegia:''' A hereditary paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.

'''Synkinesia:''' Refers to the ability to conduct voluntary movements, however, with accompanied involuntary muscular movements.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

File:Choanal atresia computed tomography 01.jpg

2012-10-01T02:31:02Z

Z3374215:

==Choanal Atresia==

Axial computed tomography

* long arrow - widening of the vomer
* short arrow - bowing of the posteromedial maxilla
* ring - narrowing of the choana anterior to the pterygoid

Original image name: Figure 1 IJPED2011-280763.001.jpg

===Reference===

<pubmed>21772853</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3134835 PMC3134835]

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

{{Template:Student Image}}

[[Category:Human]] [[Category:Abnormal Development]] [[Category:Computed Tomography]]

File:Choanal atresia computed tomography 01.jpg

2012-10-01T02:30:49Z

Z3374215:

==Choanal Atresia==

Axial computed tomography

* long arrow - widening of the vomer
* short arrow - bowing of the posteromedial maxilla
* ring - narrowing of the choana anterior to the pterygoid

Original image name: Figure 1 IJPED2011-280763.001.jpg

{{Template:Student Image}}

===Reference===

<pubmed>21772853</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3134835 PMC3134835]

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

[[Category:Human]] [[Category:Abnormal Development]] [[Category:Computed Tomography]]

2012 Group Project 4

2012-10-01T02:22:33Z

Z3374215: /* History of Discovery */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
| Discovery of [[#Glossary|Vomeronasal organ]] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|hypogonadism]] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|epiblast]], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of [[#Glossary|ectoderm]]<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|cribriform plate]]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|Kallmann's Syndrome]]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia, midline anatomic defect) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for their work on the olfactory system<ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribriform plate ====

The cribriform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribriform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

[http://www.youtube.com/watch?v=ABw68BsCMCs| http://www.youtube.com/watch?v=fIFWt6WWYO0&feature=related]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* [[#Glossary |'''Cryptorchidism''']] (males)
* [[#Glossary |'''Gynaecomastia''']] (males)
* Absence of menstruation, amennorhoea (femaleS)

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* [[#Glossary |'''Unilateral renal aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* [[#Glossary |'''Pes cavus''']] <ref name="PMID16932275"/>
* Neurological symptoms
** [[#Glossary |'''Synkinesia''']]
** Abnormalities in eye movement
** [[#Glossary |'''Cerebellar ataxia''']]
** Evoked horizontal [[#Glossary |'''nystagmus''']]
** Sensorineural deafness
** Spatial attentional abnormalities
** [[#Glossary |'''Spastic paraplegia''']]
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>
===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
A [http://www.ncbi.nlm.nih.gov/pubmed/21543621 paper]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]]Another [http://www.ncbi.nlm.nih.gov/pubmed/21943152 paper] also investigating the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
A [http://www.ncbi.nlm.nih.gov/pubmed/22906231 study] from August this year looked into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular part of the research looking to determine whether Neurog1 and Neurog2 were required for olfactory bulb development utilised a loss-of-function technique to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cryptorchidism:''' Failure of one or both testes to migrate into the scrotum during male foetus development.

'''Ectoderm:''' The outermost layer of the trilaminar embryo. Differentiates to form structures including the epidermis and neural tissue.

'''Epiblast:''' The collective term for embryonic mesoderm and ectoderm before differentiation

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Gynaecomastia:''' The development of abnormal mammary glands in males characterised by enlarged breasts.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nystagmus:''' Refers to fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Pes cavus:''' A deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. Also referred to as clawfoot.

'''Spastic paraplegia:''' A hereditary paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.

'''Synkinesia:''' Refers to the ability to conduct voluntary movements, however, with accompanied involuntary muscular movements.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-10-01T02:20:48Z

Z3374215: /* Glossary */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
| Discovery of [[#Glossary|Vomeronasal organ]] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|hypogonadism]] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|epiblast]], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of ectoderm<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|cribriform plate]]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|Kallmann's Syndrome]]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia, midline anatomic defect) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for their work on the olfactory system<ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribriform plate ====

The cribriform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribriform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

[http://www.youtube.com/watch?v=ABw68BsCMCs| http://www.youtube.com/watch?v=fIFWt6WWYO0&feature=related]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* [[#Glossary |'''Cryptorchidism''']] (males)
* [[#Glossary |'''Gynaecomastia''']] (males)
* Absence of menstruation, amennorhoea (femaleS)

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* [[#Glossary |'''Unilateral renal aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* [[#Glossary |'''Pes cavus''']] <ref name="PMID16932275"/>
* Neurological symptoms
** [[#Glossary |'''Synkinesia''']]
** Abnormalities in eye movement
** [[#Glossary |'''Cerebellar ataxia''']]
** Evoked horizontal [[#Glossary |'''nystagmus''']]
** Sensorineural deafness
** Spatial attentional abnormalities
** [[#Glossary |'''Spastic paraplegia''']]
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>
===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
A [http://www.ncbi.nlm.nih.gov/pubmed/21543621 paper]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]]Another [http://www.ncbi.nlm.nih.gov/pubmed/21943152 paper] also investigating the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
A [http://www.ncbi.nlm.nih.gov/pubmed/22906231 study] from August this year looked into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular part of the research looking to determine whether Neurog1 and Neurog2 were required for olfactory bulb development utilised a loss-of-function technique to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cryptorchidism:''' Failure of one or both testes to migrate into the scrotum during male foetus development.

'''Ectoderm:''' The outermost layer of the trilaminar embryo. Differentiates to form structures including the epidermis and neural tissue.

'''Epiblast:''' The collective term for embryonic mesoderm and ectoderm before differentiation

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Gynaecomastia:''' The development of abnormal mammary glands in males characterised by enlarged breasts.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nystagmus:''' Refers to fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Pes cavus:''' A deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. Also referred to as clawfoot.

'''Spastic paraplegia:''' A hereditary paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.

'''Synkinesia:''' Refers to the ability to conduct voluntary movements, however, with accompanied involuntary muscular movements.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-10-01T02:17:10Z

Z3374215: /* History of Discovery */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
| Discovery of [[#Glossary|Vomeronasal organ]] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|hypogonadism]] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|epiblast]], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of ectoderm<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|cribriform plate]]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|Kallmann's Syndrome]]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia, midline anatomic defect) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for their work on the olfactory system<ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribriform plate ====

The cribriform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribriform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

[http://www.youtube.com/watch?v=ABw68BsCMCs| http://www.youtube.com/watch?v=fIFWt6WWYO0&feature=related]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* [[#Glossary |'''Cryptorchidism''']] (males)
* [[#Glossary |'''Gynaecomastia''']] (males)
* Absence of menstruation, amennorhoea (femaleS)

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* [[#Glossary |'''Unilateral renal aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* [[#Glossary |'''Pes cavus''']] <ref name="PMID16932275"/>
* Neurological symptoms
** [[#Glossary |'''Synkinesia''']]
** Abnormalities in eye movement
** [[#Glossary |'''Cerebellar ataxia''']]
** Evoked horizontal [[#Glossary |'''nystagmus''']]
** Sensorineural deafness
** Spatial attentional abnormalities
** [[#Glossary |'''Spastic paraplegia''']]
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>
===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
A [http://www.ncbi.nlm.nih.gov/pubmed/21543621 paper]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]]Another [http://www.ncbi.nlm.nih.gov/pubmed/21943152 paper] also investigating the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
A [http://www.ncbi.nlm.nih.gov/pubmed/22906231 study] from August this year looked into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular part of the research looking to determine whether Neurog1 and Neurog2 were required for olfactory bulb development utilised a loss-of-function technique to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cryptorchidism:''' Failure of one or both testes to migrate into the scrotum during male foetus development.

'''Epiblast:''' The collective term for embryonic mesoderm and ectoderm before differentiation

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Gynaecomastia:''' The development of abnormal mammary glands in males characterised by enlarged breasts.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nystagmus:''' Refers to fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Pes cavus:''' A deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. Also referred to as clawfoot.

'''Spastic paraplegia:''' A hereditary paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.

'''Synkinesia:''' Refers to the ability to conduct voluntary movements, however, with accompanied involuntary muscular movements.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-10-01T02:16:17Z

Z3374215: /* Glossary */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
| Discovery of [[#Glossary|Vomeronasal organ]] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|hypogonadism]] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|epiblast]], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of ectoderm<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|cribriform plate]]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|Kallmann's Syndrome]]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia, midline anatomic defect) but he termed the condition olfactogenital [[#Glossary|dysplasia]] suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for their work on the olfactory system<ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribriform plate ====

The cribriform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribriform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

[http://www.youtube.com/watch?v=ABw68BsCMCs| http://www.youtube.com/watch?v=fIFWt6WWYO0&feature=related]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* [[#Glossary |'''Cryptorchidism''']] (males)
* [[#Glossary |'''Gynaecomastia''']] (males)
* Absence of menstruation, amennorhoea (femaleS)

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* [[#Glossary |'''Unilateral renal aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* [[#Glossary |'''Pes cavus''']] <ref name="PMID16932275"/>
* Neurological symptoms
** [[#Glossary |'''Synkinesia''']]
** Abnormalities in eye movement
** [[#Glossary |'''Cerebellar ataxia''']]
** Evoked horizontal [[#Glossary |'''nystagmus''']]
** Sensorineural deafness
** Spatial attentional abnormalities
** [[#Glossary |'''Spastic paraplegia''']]
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>
===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
A [http://www.ncbi.nlm.nih.gov/pubmed/21543621 paper]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]]Another [http://www.ncbi.nlm.nih.gov/pubmed/21943152 paper] also investigating the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
A [http://www.ncbi.nlm.nih.gov/pubmed/22906231 study] from August this year looked into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular part of the research looking to determine whether Neurog1 and Neurog2 were required for olfactory bulb development utilised a loss-of-function technique to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cryptorchidism:''' Failure of one or both testes to migrate into the scrotum during male foetus development.

'''Epiblast:''' The collective term for embryonic mesoderm and ectoderm before differentiation

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Gynaecomastia:''' The development of abnormal mammary glands in males characterised by enlarged breasts.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nystagmus:''' Refers to fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Pes cavus:''' A deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. Also referred to as clawfoot.

'''Spastic paraplegia:''' A hereditary paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.

'''Synkinesia:''' Refers to the ability to conduct voluntary movements, however, with accompanied involuntary muscular movements.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-10-01T02:12:32Z

Z3374215: /* Migratory Path of GnRH */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
| Discovery of [[#Glossary|Vomeronasal organ]] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|hypogonadism]] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|epiblast]], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of ectoderm<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|cribriform plate]]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|Kallmann's Syndrome]]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia, midline anatomic defect) but he termed the condition olfactogenital [[#Glossary|dysplasia]] suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for their work on the olfactory system<ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribriform plate ====

The cribriform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribriform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

[http://www.youtube.com/watch?v=ABw68BsCMCs| http://www.youtube.com/watch?v=fIFWt6WWYO0&feature=related]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* [[#Glossary |'''Cryptorchidism''']] (males)
* [[#Glossary |'''Gynaecomastia''']] (males)
* Absence of menstruation, amennorhoea (femaleS)

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* [[#Glossary |'''Unilateral renal aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* [[#Glossary |'''Pes cavus''']] <ref name="PMID16932275"/>
* Neurological symptoms
** [[#Glossary |'''Synkinesia''']]
** Abnormalities in eye movement
** [[#Glossary |'''Cerebellar ataxia''']]
** Evoked horizontal [[#Glossary |'''nystagmus''']]
** Sensorineural deafness
** Spatial attentional abnormalities
** [[#Glossary |'''Spastic paraplegia''']]
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>
===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
A [http://www.ncbi.nlm.nih.gov/pubmed/21543621 paper]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]]Another [http://www.ncbi.nlm.nih.gov/pubmed/21943152 paper] also investigating the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
A [http://www.ncbi.nlm.nih.gov/pubmed/22906231 study] from August this year looked into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular part of the research looking to determine whether Neurog1 and Neurog2 were required for olfactory bulb development utilised a loss-of-function technique to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomeronasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cryptorchidism:''' Failure of one or both testes to migrate into the scrotum during male foetus development.

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Gynaecomastia:''' The development of abnormal mammary glands in males characterised by enlarged breasts.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nystagmus:''' Refers to fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Pes cavus:''' A deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. Also referred to as clawfoot.

'''Spastic paraplegia:''' A hereditary paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.

'''Synkinesia:''' Refers to the ability to conduct voluntary movements, however, with accompanied involuntary muscular movements.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-10-01T02:11:27Z

Z3374215: /* Timeline of developmental process */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
| Discovery of [[#Glossary|Vomeronasal organ]] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|hypogonadism]] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|epiblast]], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of ectoderm<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|cribriform plate]]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|Kallmann's Syndrome]]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia, midline anatomic defect) but he termed the condition olfactogenital [[#Glossary|dysplasia]] suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for their work on the olfactory system<ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribriform plate ====

The cribriform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribriform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

[http://www.youtube.com/watch?v=ABw68BsCMCs| http://www.youtube.com/watch?v=fIFWt6WWYO0&feature=related]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426">Treloar HB, Miller AM, Ray A, et al. Development of the Olfactory System. In: Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press; 2010. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55972/</ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* [[#Glossary |'''Cryptorchidism''']] (males)
* [[#Glossary |'''Gynaecomastia''']] (males)
* Absence of menstruation, amennorhoea (femaleS)

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* [[#Glossary |'''Unilateral renal aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* [[#Glossary |'''Pes cavus''']] <ref name="PMID16932275"/>
* Neurological symptoms
** [[#Glossary |'''Synkinesia''']]
** Abnormalities in eye movement
** [[#Glossary |'''Cerebellar ataxia''']]
** Evoked horizontal [[#Glossary |'''nystagmus''']]
** Sensorineural deafness
** Spatial attentional abnormalities
** [[#Glossary |'''Spastic paraplegia''']]
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>
===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
A [http://www.ncbi.nlm.nih.gov/pubmed/21543621 paper]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]]Another [http://www.ncbi.nlm.nih.gov/pubmed/21943152 paper] also investigating the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
A [http://www.ncbi.nlm.nih.gov/pubmed/22906231 study] from August this year looked into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular part of the research looking to determine whether Neurog1 and Neurog2 were required for olfactory bulb development utilised a loss-of-function technique to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomernasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cryptorchidism:''' Failure of one or both testes to migrate into the scrotum during male foetus development.

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Gynaecomastia:''' The development of abnormal mammary glands in males characterised by enlarged breasts.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nystagmus:''' Refers to fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Pes cavus:''' A deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. Also referred to as clawfoot.

'''Spastic paraplegia:''' A hereditary paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.

'''Synkinesia:''' Refers to the ability to conduct voluntary movements, however, with accompanied involuntary muscular movements.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-10-01T02:07:13Z

Z3374215: /* History of Discovery */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
| Discovery of [[#Glossary|Vomeronasal organ]] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|hypogonadism]] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|epiblast]], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of ectoderm<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform plate|cribriform plate]]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|Kallmann's Syndrome]]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia, midline anatomic defect) but he termed the condition olfactogenital [[#Glossary|dysplasia]] suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for their work on the olfactory system<ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribriform plate ====

The cribriform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribriform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

[http://www.youtube.com/watch?v=ABw68BsCMCs| http://www.youtube.com/watch?v=fIFWt6WWYO0&feature=related]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426"><pubmed>21882426</pubmed></ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* [[#Glossary |'''Cryptorchidism''']] (males)
* [[#Glossary |'''Gynaecomastia''']] (males)
* Absence of menstruation, amennorhoea (femaleS)

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* [[#Glossary |'''Unilateral renal aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* [[#Glossary |'''Pes cavus''']] <ref name="PMID16932275"/>
* Neurological symptoms
** [[#Glossary |'''Synkinesia''']]
** Abnormalities in eye movement
** [[#Glossary |'''Cerebellar ataxia''']]
** Evoked horizontal [[#Glossary |'''nystagmus''']]
** Sensorineural deafness
** Spatial attentional abnormalities
** [[#Glossary |'''Spastic paraplegia''']]
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>
===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
A [http://www.ncbi.nlm.nih.gov/pubmed/21543621 paper]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]]Another [http://www.ncbi.nlm.nih.gov/pubmed/21943152 paper] also investigating the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
A [http://www.ncbi.nlm.nih.gov/pubmed/22906231 study] from August this year looked into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular part of the research looking to determine whether Neurog1 and Neurog2 were required for olfactory bulb development utilised a loss-of-function technique to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomernasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cryptorchidism:''' Failure of one or both testes to migrate into the scrotum during male foetus development.

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Gynaecomastia:''' The development of abnormal mammary glands in males characterised by enlarged breasts.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nystagmus:''' Refers to fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Pes cavus:''' A deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. Also referred to as clawfoot.

'''Spastic paraplegia:''' A hereditary paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.

'''Synkinesia:''' Refers to the ability to conduct voluntary movements, however, with accompanied involuntary muscular movements.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-10-01T02:05:02Z

Z3374215: /* Cribriform plate */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
| Discovery of [[#Glossary|Vomeronasal organ]] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|hypogonadism]] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|epiblast]], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of ectoderm<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform Plate|cribriform plate]]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|Kallmann's Syndrome]]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia, midline anatomic defect) but he termed the condition olfactogenital [[#Glossary|dysplasia]] suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for their work on the olfactory system<ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribriform plate ====

The cribriform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribriform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

[http://www.youtube.com/watch?v=ABw68BsCMCs| http://www.youtube.com/watch?v=fIFWt6WWYO0&feature=related]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426"><pubmed>21882426</pubmed></ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* [[#Glossary |'''Cryptorchidism''']] (males)
* [[#Glossary |'''Gynaecomastia''']] (males)
* Absence of menstruation, amennorhoea (femaleS)

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* [[#Glossary |'''Unilateral renal aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* [[#Glossary |'''Pes cavus''']] <ref name="PMID16932275"/>
* Neurological symptoms
** [[#Glossary |'''Synkinesia''']]
** Abnormalities in eye movement
** [[#Glossary |'''Cerebellar ataxia''']]
** Evoked horizontal [[#Glossary |'''nystagmus''']]
** Sensorineural deafness
** Spatial attentional abnormalities
** [[#Glossary |'''Spastic paraplegia''']]
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>
===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
A [http://www.ncbi.nlm.nih.gov/pubmed/21543621 paper]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]]Another [http://www.ncbi.nlm.nih.gov/pubmed/21943152 paper] also investigating the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
A [http://www.ncbi.nlm.nih.gov/pubmed/22906231 study] from August this year looked into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular part of the research looking to determine whether Neurog1 and Neurog2 were required for olfactory bulb development utilised a loss-of-function technique to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomernasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cryptorchidism:''' Failure of one or both testes to migrate into the scrotum during male foetus development.

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Gynaecomastia:''' The development of abnormal mammary glands in males characterised by enlarged breasts.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nystagmus:''' Refers to fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Pes cavus:''' A deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. Also referred to as clawfoot.

'''Spastic paraplegia:''' A hereditary paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.

'''Synkinesia:''' Refers to the ability to conduct voluntary movements, however, with accompanied involuntary muscular movements.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-10-01T02:04:10Z

Z3374215: /* Cribiform plate */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
| Discovery of [[#Glossary|Vomeronasal organ]] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|hypogonadism]] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|epiblast]], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of ectoderm<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform Plate|cribriform plate]]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|Kallmann's Syndrome]]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia, midline anatomic defect) but he termed the condition olfactogenital [[#Glossary|dysplasia]] suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for their work on the olfactory system<ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribriform plate ====

The cribiform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribiform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

[http://www.youtube.com/watch?v=ABw68BsCMCs| http://www.youtube.com/watch?v=fIFWt6WWYO0&feature=related]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426"><pubmed>21882426</pubmed></ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* [[#Glossary |'''Cryptorchidism''']] (males)
* [[#Glossary |'''Gynaecomastia''']] (males)
* Absence of menstruation, amennorhoea (femaleS)

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* [[#Glossary |'''Unilateral renal aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* [[#Glossary |'''Pes cavus''']] <ref name="PMID16932275"/>
* Neurological symptoms
** [[#Glossary |'''Synkinesia''']]
** Abnormalities in eye movement
** [[#Glossary |'''Cerebellar ataxia''']]
** Evoked horizontal [[#Glossary |'''nystagmus''']]
** Sensorineural deafness
** Spatial attentional abnormalities
** [[#Glossary |'''Spastic paraplegia''']]
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>
===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
A [http://www.ncbi.nlm.nih.gov/pubmed/21543621 paper]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]]Another [http://www.ncbi.nlm.nih.gov/pubmed/21943152 paper] also investigating the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
A [http://www.ncbi.nlm.nih.gov/pubmed/22906231 study] from August this year looked into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular part of the research looking to determine whether Neurog1 and Neurog2 were required for olfactory bulb development utilised a loss-of-function technique to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomernasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cryptorchidism:''' Failure of one or both testes to migrate into the scrotum during male foetus development.

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Gynaecomastia:''' The development of abnormal mammary glands in males characterised by enlarged breasts.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nystagmus:''' Refers to fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Pes cavus:''' A deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. Also referred to as clawfoot.

'''Spastic paraplegia:''' A hereditary paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.

'''Synkinesia:''' Refers to the ability to conduct voluntary movements, however, with accompanied involuntary muscular movements.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-10-01T02:02:01Z

Z3374215: /* History of Discovery */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
| Discovery of [[#Glossary|Vomeronasal organ]] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [[#Glossary|hypogonadism]] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [[#Glossary|epiblast]], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of ectoderm<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [[#Cribriform Plate|cribriform plate]]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|Kallmann's Syndrome]]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia, midline anatomic defect) but he termed the condition olfactogenital [[#Glossary|dysplasia]] suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for their work on the olfactory system<ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribiform plate ====

The cribiform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribiform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

[http://www.youtube.com/watch?v=ABw68BsCMCs| http://www.youtube.com/watch?v=fIFWt6WWYO0&feature=related]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426"><pubmed>21882426</pubmed></ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* [[#Glossary |'''Cryptorchidism''']] (males)
* [[#Glossary |'''Gynaecomastia''']] (males)
* Absence of menstruation, amennorhoea (femaleS)

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* [[#Glossary |'''Unilateral renal aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* [[#Glossary |'''Pes cavus''']] <ref name="PMID16932275"/>
* Neurological symptoms
** [[#Glossary |'''Synkinesia''']]
** Abnormalities in eye movement
** [[#Glossary |'''Cerebellar ataxia''']]
** Evoked horizontal [[#Glossary |'''nystagmus''']]
** Sensorineural deafness
** Spatial attentional abnormalities
** [[#Glossary |'''Spastic paraplegia''']]
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>
===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
A [http://www.ncbi.nlm.nih.gov/pubmed/21543621 paper]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]]Another [http://www.ncbi.nlm.nih.gov/pubmed/21943152 paper] also investigating the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
A [http://www.ncbi.nlm.nih.gov/pubmed/22906231 study] from August this year looked into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular part of the research looking to determine whether Neurog1 and Neurog2 were required for olfactory bulb development utilised a loss-of-function technique to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomernasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cryptorchidism:''' Failure of one or both testes to migrate into the scrotum during male foetus development.

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Gynaecomastia:''' The development of abnormal mammary glands in males characterised by enlarged breasts.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nystagmus:''' Refers to fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Pes cavus:''' A deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. Also referred to as clawfoot.

'''Spastic paraplegia:''' A hereditary paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.

'''Synkinesia:''' Refers to the ability to conduct voluntary movements, however, with accompanied involuntary muscular movements.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-10-01T02:00:17Z

Z3374215: /* History of Discovery */

[[File:Antony_smelling_flower.jpg|800px|right]]

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
| Discovery of [[#Glossary|Vomeronasal organ]] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link [#Glossary|hypogonadism] to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of [#Glossary|epiblast], the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of ectoderm<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the [#Cribriform Plate|cribriform plate]<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|Kallmann's Syndrome]]. Frank Kallmann was a geneticist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia, midline anatomic defect) but he termed the condition olfactogenital [#Glossary|dysplasia] suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for their work on the olfactory system<ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|215px|thumb|left|Cribiform plate and Olfactory Bulb/Epithelium]]

==== Nasal Cavity ====

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found.
These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide.
Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells.
The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia.
The Olfactory vesicles are also known to serve in the process of stimulus transduction.

[[File:Olfactory_epithelium.jpg|400px|thumb|right|Olfactory Epithelium]]

==== Olfactory Epithelium ====

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain. It consists of 3 different cell types, namely basal, supporting and olfactory receptor cells as shown in the diagram to the right.
Basal cells are stem cells which give rise to olfactory receptor cells.
The continuous supply of neurons and the replacement of neurons by less differentiated stem cells is unique only to the olfactory system.
The third type of cells is the supporting cells which are found among the receptor cells and their function is to empty their content onto the mucosal surface using their microvili and secretory granules.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|380px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

==== Cribiform plate ====

The cribiform plate is composed of the ethmoid bone and acts as the roof of the nasal cavity. The plate is narrow and deeply grooved as it acts as a support structure for the olfactory bulb, and pierced by a foramina to allow the passage of olfactory nerves through the plate. The foramina located in the middle of the grove allows the passage of nerves through the roof of the nasal cavity, whereas the the foramina on the medial parts of the groow allows the passage of nerves to the superior part of nasal septum. The foramina located on the lateral side of the grove also permits the passage of nerves and direct them towards superior nasal concha.

If the cribiform plate is fractured, it can lead to the loss of sense of smell and the leaking of cerebrospinal fluid into the nose.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

[http://www.youtube.com/watch?v=ABw68BsCMCs| http://www.youtube.com/watch?v=fIFWt6WWYO0&feature=related]

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain(mesencephalon) and forebrain(prosencephalon)<ref name="PMID21882426"><pubmed>21882426</pubmed></ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon produced cells which migrated to the frontonasal mass while anterior neural crest cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>

||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||

FGF plays a role in signalling the generation of olfactory sensory epithelium. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.<ref name="PMID438867"><pubmed>438867</pubmed></ref>
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

'''Primitive choana''': formed as the oronasal membrane ruptures. <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
BMP plays a role in signalling the generation of non-sensory epithelium.<ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline . <ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
image

|}

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* [[#Glossary |'''Cryptorchidism''']] (males)
* [[#Glossary |'''Gynaecomastia''']] (males)
* Absence of menstruation, amennorhoea (femaleS)

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* [[#Glossary |'''Unilateral renal aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* [[#Glossary |'''Pes cavus''']] <ref name="PMID16932275"/>
* Neurological symptoms
** [[#Glossary |'''Synkinesia''']]
** Abnormalities in eye movement
** [[#Glossary |'''Cerebellar ataxia''']]
** Evoked horizontal [[#Glossary |'''nystagmus''']]
** Sensorineural deafness
** Spatial attentional abnormalities
** [[#Glossary |'''Spastic paraplegia''']]
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>
===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
A [http://www.ncbi.nlm.nih.gov/pubmed/21543621 paper]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]]Another [http://www.ncbi.nlm.nih.gov/pubmed/21943152 paper] also investigating the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
A [http://www.ncbi.nlm.nih.gov/pubmed/22906231 study] from August this year looked into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular part of the research looking to determine whether Neurog1 and Neurog2 were required for olfactory bulb development utilised a loss-of-function technique to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomernasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cryptorchidism:''' Failure of one or both testes to migrate into the scrotum during male foetus development.

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Gynaecomastia:''' The development of abnormal mammary glands in males characterised by enlarged breasts.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nystagmus:''' Refers to fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Pes cavus:''' A deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. Also referred to as clawfoot.

'''Spastic paraplegia:''' A hereditary paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.

'''Synkinesia:''' Refers to the ability to conduct voluntary movements, however, with accompanied involuntary muscular movements.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

User:Z3374215

2012-10-01T01:50:59Z

Z3374215:

==Lab Attendance==

Lab 1 --[[User:Z3374215|Z3374215]] 11:49, 25 July 2012 (EST)

Lab 2 --[[User:Z3374215|Z3374215]] 10:06, 1 August 2012 (EST)

Lab 3 --[[User:Z3374215|Z3374215]] 10:06, 8 August 2012 (EST)

Lab 4 --[[User:Z3374215|Z3374215]] 12:01, 15 August 2012 (EST)

Lab 5 --[[User:Z3374215|Z3374215]] 10:05, 22 August 2012 (EST)

Lab 6 --[[User:Z3374215|Z3374215]] 10:08, 29 August 2012 (EST)

Lab 7 --[[User:Z3374215|Z3374215]] 10:14, 12 September 2012 (EST)

Lab 8 --[[User:Z3374215|Z3374215]] 11:34, 19 September 2012 (EST)

Lab 9 --[[User:Z3374215|Z3374215]] 10:10, 26 September 2012 (EST)

==Lab 1 Assessment==
'''1) Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.'''

The Nobel Prize for physiology or medicine in 2010 was awarded to Robert G. Edwards for his efforts in the development of In Vitro fertilization. Robert G. Edwards developed the idea of In Vitro fertilization since the 1950s. He first made fundamental discoveries in the life cycles of human eggs and the optimal time for fertilization before pairing with a gynecologist, Patrick Steptoe, and eventually seeing to the successful birth of an IVF baby in 1978. <ref>http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html</ref>.

'''2) Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).
'''
"The relative contributions of propulsive forces and receptor-ligand binding forces during early contact between spermatozoa and zona pellucida of oocyte" was published by the Journal of Theoretical Biology in Nov. 2011 <ref name= 'PMID22100500"><pubmed>22100500</pubmed></ref>. This report discusses the two main ways in which spermatozoa penetrate the zona pellucida of oocytes. The sperm utilize propulsive forces to assist in penetration. This is achieved through the motion of the flagella. The other factor important to penetration is the binding of sperm to ligands on the surface of the zona pellucida of the oocyte (ZP3). The report addresses the question of which of the cofactors is most imperative to the successful fertilization of the oocyte. A biomechanical model of the sperm-oocyte process was developed. It predicted that during early penetration the propulsive forces were stronger than the biochemical ligand binding. It was also predicted that the constant movement and overpowering force of the propulsion of sperm would make binding to ZP3 ligands difficult, making the large number of ZP3 receptors on the head of the sperm significantly important at this early stage.

===References===
<references/>

==Lab 2 Assessment==
'''1) Upload an image from a journal source relating to fertilization or the first 2 weeks of development as demonstrated in the practical class. Including in the image “Summary” window: An image name as a section heading, Any further description of what the image shows, A subsection labeled “Reference” and under this the original image source, appropriate reference and all copyright information and finally a template indicating that this is a student image.'''

'''Image:''' Expression of Endometrial CD98 in implantation<ref name:"PMID20976164"><pubmed>20976164</pubmed></ref>
[[Image:Expression of Endometrial CD98 in implantation.png|thumb|center|alt=Alt|Expression of Endometrial CD98 in implantation]]

'''2) Identify a protein associated with the implantation process, including a brief description of the protein's role (1-2 paragraphs).'''

A study has identified trophinin as a protein important to the adhesion implantation process. It is believed to be a single intrinsic protein that spans the membrane due to hydrophobic tendencies. This molecule can adhere without the aid of calcium unlike many cell adhesion molecules. Trophinin molecules bind with other trophinin molecule in trans structure on the cell surface. Immunostaining showed that antigens specific to the trophinin molecule can be found in both trophoblast cells and in the maternal epithelium near implantation sites of the embryo. The protein has been found to be encoded in the short arm of the X chromosome. It is also present in the mouse, sheep and bovine, along with monotremes and marsupials. It appears that the binding of the trophectoderm (consists of trophoblasts and is the connection between the blastocyst and the maternal cells) is essential to invasion and proliferation of cells. In embryonic cells trophinin induces and promotes invasion and proliferation. In maternal cells the same protein promotes apoptosis (controlled cell death) so as to allow the acceptance of the embryo. Therefore it is a dual signalling molecule. <ref name="PMID22717627"><pubmed>22717627</pubmed></ref>

===Reference===
<references/>

==Lab 3 Assessment==

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

The gestational age refers to the time since the last normal menstruation period<ref>Moore, K.L., 2011 ''The Developing Human'' 9th ed. W.B. Saunders</ref>. Whereas post-fertilisation age is calculated from the time of fertilization. There can be confusion between the terms espcially as gestational age is two weeks longer than post-fertilisation age<ref name:"PMID"15520122"><pubmed>15520122,</pubmed></ref>. Although in itself the term gestation age is confusing as there is no actual conceptus in until fertilisation but it is accepted by clinicians through widespread use<ref name:"PMID16006453"><pubmed>16006453</pubmed></ref>. As exact post-fetilisation age would be difficult to determine gestational age is used clinically. In assisted reproduction cases post-fertilisation age can be accurately determined but 2 weeks are generally added to age for ease of understanding<ref name:"PMID"15520122"><pubmed>15520122,</pubmed></ref>.

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

Somites form the dermis of the dorsal epithelium, skeletal muscles and some connective tissue, specifically, the vertebrae and ribs.<ref>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Paraxial Mesoderm: The Somites and Their Derivatives. Available from: http://www.ncbi.nlm.nih.gov/books/NBK10085/</ref>

===References===
<references/>

==Lab 4 Assessment==
'''1) Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.'''
Prenatal placental biopsy an invasive diagnostic technique for genetic abnormalities (such as trisomy 21) in the fetus. A karyotype is constructed allowing analysis of the chromosomes. It is used in the second and third trimester of pregnancy to confirm suspected malformations. Placental biopsies are sonographically guided<ref name:"PMID2712602"><pubmed>2712602</pubmed></ref>.
Chorionic villus testing is another invasive technique carried out transcervically in the first trimester to detect inherited disorders such as haemophilia <ref name:"PMID22250892"><pubmed>22250892</pubmed></ref>

'''2) Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''
Mesenchymal stem cells derived from the human umbilical cord have been used as a therapeutic treatment for neuromyelitis optica. Neuromyelitis optica is an autoimmune inflammatory disease that effects the optic nerve and spinal cord. Stem cells have been seen to provide differentiation potential to neural cells, secrete necessary factors and help regulate immunological function.
Five patients were treated with stem cell injections and then monitored for 18 months to analyse the effects both adverse and any improvements. Four out of the five patients gained some relief following treatment. Signs and symptoms decreased and the frequency of relapse was lessened. The neurological lesions also decreased in volume and severity as seen by MRI. The paper summarised that human umbilical cord stem cells were an appropriate therapy technique<ref name:"PMID22873728"><pubmed>22873728</pubmed></ref>.

===References===
<references/>

==Lab 7 Assessment==
'''1. (a) Provide a one sentence definition of a muscle satellite cell'''

Muscle satellite cells are progenitor cells and are involved in muscle growth and repair as they can induce regenerated muscle and additional satellite cells<ref name:”PMID12757751”><pubmed>12757751</pubmed></ref>

'''(b) In one paragraph, briefly discuss two examples of when satellite cells are activated.'''

A study investigating exercised induced satellite cell activation in skeletal muscle of growing and mature rats concluded that satellite cells are activated by acute sessions of prolonged eccentric exercise. It also concluded that exercise affected the proliferation of young mitotically active satellite cells<ref name:”PMID3693217”><pubmed>3693217</pubmed></ref>. Satellite cells are also activated when damage occurs. A study indicated that two variants of the IGF-I gene are necessary for activation of satellite cells. The study examined induced lesions to the anterior tibialis muscle of rats. The results showed that one variant of the gene which gives rise to a growth factor, MGF, is initially produced after injury and it activates satellite cells then IGF-IEa is expressed to maintain the repair process <ref>M Hill1, A Wernig, G Goldspink '''Muscle satellite (stem) cell activation during local tissue injury and repair''' Journal of Anatomy:2003, 203(1);89-99</ref>

'''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.'''

In a study involving 12 human patients suffering from spinal cord injuries a section of the vastus lateralis muscle was biopsied at 3 intervals within the first 6month following injury. From 6-24 weeks after injury they showed 27-56% atrophy of Type I, IIa and IIax+IIx fibers. There was increased conversion between muscle types, type IIa decreased and type IIax+IIx increased. However there was little change in proportion of tpye I fibers during this period<ref name:"PMID9887150"><pubmed>9887150</pubmed></ref>

===Reference===
<references/>

==Lab 8 Assessment - Peer Review==
===Vision===
The layout of the page is relatively good. If anything it appears little too image heavy at the moment. On the note of images, the referencing is good but don't forget to include the student template note with each image. The inclusion of some student drawn images in great to see but it might be an idea to make the labels larger as they are hard to read. The use of subheadings is great, a really logically well set out page. The references need a bit of work, some are spread sporadically throughout the page and some in the references section just list the URL along with the error on reference number 13.

The introductory is brief but alright. However the first two images are largely similar, not sure why both need to be included. Perhaps if possible it would be nice to link each of the main anatomical bullet points you have listed in your introduction to their associated developmental paragraph further down the page.

The History of development is coming along nicely but perhaps would be easier to read if it was in the format of a table. Also the Atlas of the Development of Man needs to be properly referenced with the author in the reference section. It would be nice to have some information relating to the pictures uploaded in this section.

The section on Development is well done and it is interesting to look at the individual development of each structure. It might be an idea to include some more references to when each structural development occurs. Current Research really needs some more content. The glossary is a nice addition and helpful.

===Somatosensory===
This page has made good use of subheadings ensuring that the main topics are easily accessible from the contents box. The project appears a little text heavy, it may help to include some other images. Also don't forget to add the student template note on the student drawn image. The reference list at the end is not particularly extensive. Perhaps this can be worked on by collecting the loose references in the text and adding them to the final reference section. Overall some sections of the page seem to have little to with embryology and more focused on adult function.

The introduction, while good, seems to lack any original voice, rather seeming to consist almost entirely of research done by others. The referencing in this section is also confusing with (Lagercrantz, Hanson, Evrard & Rodeck, 2001) being listed before any text. Referencing in this format also makes the page seem like a report or essay rather than a web page. There is also mention of a picture that does not exist. The historic section is brief and rather hard to digest as it is just a chunk of text. Perhaps putting this information into a table and developing it a little would help here.

The section on Central Somatosensory Differentiation was particularly well done. The inclusion of the student drawn image making all the difference. The general structure of this section is also commendable.

The subtitles "Touch", "Pain", "Heat/Cold" and "Pressure" are somewhat abrupt and don't particularly indicate what the section is discussing. This section in particular could do with the addition of some images. The information under Touch could perhaps be a little more heavily researched but is generally well written. Breaking the Pain section into some smaller paragraphs could be useful. The Hot/Cold and Pressure sections are well done excepting the random references to some articles.

Current research section could do with some more information. There are several words throughout the content that could do with being linked to an explanation in the glossary such as the "dorsal column-medial lemniscal system". The external links section is a good addition but it might be helpful to explain more clearly what each links to, especially the last three.

===Taste===
Initially the page seems to have a good balance between text and diagrams/photographs. However the figures included are not properly labelled once you click on the file and some of them don't appear to have any copyright information included. Some of the pictures could do with being a bit smaller as they take up a large proportion of the page. The student drawn image of the tongue is particularly impressive but does still need to have the student template included. The references seem limited in comparison to other groups perhaps suggesting a lack of depth or variety of research. There also appears to be a coding problem relating to reference number 5. The general layout and use of subheadings is great. It may be useful to link the words in the glossary to their occurrence in the text.

The introductory paragraphs are very well written. They are easy to understand and interesting and give a good overview of how taste functions. Similarly the section on taste map is well written clearly explaining the neurological factors associated with taste. However the presence of the picture in isolation is confusing as it is representing an the old method of taste association. Perhaps this would be resolved if a diagram of the newer taste map was also included. Also you say that the old taste map has been disproved by recent research but that research is not referenced. In fact it appears that very little of that section is referenced. The section on cortical areas is well done.

The timeline of developmental processes is good, the table an easy visual format and the information concise and effective. The only point of contention would be the direct quote in Wk8-9 which seems out of place in comparison to the remainder of the entries which are nicely paraphrased. The history section is similarly well done being extensive and comprehensive. That is excepting some Pub Med references which are just placed in the text rather than in the reference list at the bottom. While interesting and well written the part detailing the Adult Tongue and Taste Buds seems out of place in a embryology course.

The sections on the effect of gene expression on the formation of taste abnormalities and current research are good. However it may be useful to put the information regarding each picture as a caption rather than plain text.

It will be interesting to see what is put in the section "Image Gallery"

===Abnormal Vision===
Your introduction is relatively well written and the brief explanation of new terms such as microphthalmia was particularly useful. Perhaps it would be possible to break the text into two paragraphs to make reading easier.
It is really good to see a section included about normal eye development as it provides a basis of understanding for the remainder of the page. Concise and to the point and not too complex, it's great. Only suggestion would be to place it in a table perhaps with each Carnegie stage a new entry.

Layout of abnormalities is very logical covering the main areas of developmental abnormalities. However it is slightly confusing that immediately under the title Abnormal Lens Development more information on normal development is given. Allocating the defects to their associated individual genes is good but perhaps instead of a dotpoint a subheading would be of more use. The actual information is clearly and effectively written. The inclusion of the pictures clearly illustrates the abnormalities but their placement is a little odd. Perhaps they are too large. The captions on the pictures are appropriate and the pictures are appropriately referenced and it is great that the link to the picture contains more information.

Under the title "Ocular Manifestations" perhaps indicate what the two sections are, just so the following on sections make sense and don't appear disjointed. The sections on the genetic caused abnormalities is fascinating and very well written. The timeline included in the information about Leber Congenital Amaurosis is particularly interesting. The spacing in the section on genes associated with Anophthalmia and Microphthalmia appears slightly strange. The figures included are particularly illustrative and appropriate. Similarly the section on environmentally caused abnormalities is really well written and interesting.

Perhaps a more extensive section on current research could be included. If possible, link the words in the glossary to where they appeared in the text. This is the coding if you don't have it [[#Glossary|'''Words for Glossary''']]. Just add that in place of the word when you first mention it in the text. The citing and referencing is really well done. It also shows a great depth of research. The figures/photographs so far included are brilliant but the inclusion of a student drawn diagram somewhere if possible would be effective. Also try and fix the general layout of the project, possibly including some more subheadings. In general the content relates to the the course and is pitched at an appropriate level. Hope this helps.

===Hearing===
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.

===Lab 9===
'''1) Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

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

2012 Group Project 4

2012-09-26T01:43:45Z

Z3374215: /* Treatment */

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
| Discovery of [[#Glossary|Vomeronasal organ]] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link hypogonadism to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of epiblast, the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of ectoderm<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the cribriform plate<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|Kallmann's Syndrome]]. Frank Kallmann was a genetist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia, midline anatomic defect) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for their work on the olfactory system<ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|200px|thumb|right|Cribiform plate and Olfactory Bulb/Epithelium]]

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found. These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide. Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells. The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia. The Olfactory vesicles are also known to serve in the process of stimulus transduction.

==== Olfactory Epithelium ====

[[File:Olfactory_epithelium.jpg|300px|thumb|right|Olfactory Epithelium]]

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|300px|thumb|right|Olfactory Bulb]]

The olfactory bulb is a structure located in the forebrain which receives neural information about odours detected by recepotor cells within the nasal cavity. The information is extended to the olfactory bulb by the axons of olfactory receptor where the information is processed, and the smell of the odour determined.

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain and forebrain<ref name="PMID21882426"><pubmed>21882426</pubmed></ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon(forebrain) produced cells which migrated to the frontonasal mass while anterior neural ridge cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region(midbrain) produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Early Notch signalling plays an important role in the inhibiton of early differentiation of olfactory epithelial cells into olfactory sensory neurons.<ref name="PMID22964415"><pubmed>22964415</pubmed></ref>
||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||
Genes
||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
Genes
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity.

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane

'''Primitive choana''': formed as the oronasal membrane ruptures.

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
Genes
||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline .
||
image

|}

EFFECT OF AMNIOTIC FLUID ON THE DEVELOPMENT OF OLFACTION IN THE FETUS still to be ncluded!

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* [[#Glossary |'''Cryptorchidism''']] (males)
* [[#Glossary |'''Gynaecomastia''']] (males)
* Absence of menstruation, amennorhoea (femaleS)

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* [[#Glossary |'''Unilateral renal aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* [[#Glossary |'''Pes cavus''']] <ref name="PMID16932275"/>
* Neurological symptoms
** [[#Glossary |'''Synkinesia''']]
** Abnormalities in eye movement
** [[#Glossary |'''Cerebellar ataxia''']]
** Evoked horizontal [[#Glossary |'''nystagmus''']]
** Sensorineural deafness
** Spatial attentional abnormalities
** [[#Glossary |'''Spastic paraplegia''']]
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>
===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
A [http://www.ncbi.nlm.nih.gov/pubmed/21543621 paper]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]]Another [http://www.ncbi.nlm.nih.gov/pubmed/21943152 paper] also investigating the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
A [http://www.ncbi.nlm.nih.gov/pubmed/22906231 study] from August this year looked into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular part of the research looking to determine whether Neurog1 and Neurog2 were required for olfactory bulb development utilised a loss-of-function technique to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomernasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cryptorchidism:''' Failure of one or both testes to migrate into the scrotum during male foetus development.

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Gynaecomastia:''' The development of abnormal mammary glands in males characterised by enlarged breasts.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nystagmus:''' Refers to fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Pes cavus:''' A deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. Also referred to as clawfoot.

'''Spastic paraplegia:''' A hereditary paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.

'''Synkinesia:''' Refers to the ability to conduct voluntary movements, however, with accompanied involuntary muscular movements.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-09-26T01:40:54Z

Z3374215: /* Diagnosis and Treatment */

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
| Discovery of [[#Glossary|Vomeronasal organ]] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link hypogonadism to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of epiblast, the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of ectoderm<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the cribriform plate<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|Kallmann's Syndrome]]. Frank Kallmann was a genetist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia, midline anatomic defect) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for their work on the olfactory system<ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|200px|thumb|right|Cribiform plate and Olfactory Bulb/Epithelium]]

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found. These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide. Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells. The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia. The Olfactory vesicles are also known to serve in the process of stimulus transduction.

==== Olfactory Epithelium ====

[[File:Olfactory_epithelium.jpg|300px|thumb|right|Olfactory Epithelium]]

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|300px|thumb|right|Olfactory Bulb]]

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain and forebrain<ref name="PMID21882426"><pubmed>21882426</pubmed></ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon(forebrain) produced cells which migrated to the frontonasal mass while anterior neural ridge cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region(midbrain) produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Genes Involved
||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||
Genes
||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
Genes
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity.

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane

'''Primitive choana''': formed as the oronasal membrane ruptures.

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
Genes
||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline .
||
image

|}

EFFECT OF AMNIOTIC FLUID ON THE DEVELOPMENT OF OLFACTION IN THE FETUS still to be ncluded!

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* [[#Glossary |'''Cryptorchidism''']] (males)
* [[#Glossary |'''Gynaecomastia''']] (males)
* Absence of menstruation, amennorhoea (femaleS)

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* [[#Glossary |'''Unilateral renal aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* [[#Glossary |'''Pes cavus''']] <ref name="PMID16932275"/>
* Neurological symptoms
** [[#Glossary |'''Synkinesia''']]
** Abnormalities in eye movement
** [[#Glossary |'''Cerebellar ataxia''']]
** Evoked horizontal [[#Glossary |'''nystagmus''']]
** Sensorineural deafness
** Spatial attentional abnormalities
** [[#Glossary |'''Spastic paraplegia''']]
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>
===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
!Diagnosis and Treatment
|-
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

====Treatment====
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
A [http://www.ncbi.nlm.nih.gov/pubmed/21543621 paper]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]]Another [http://www.ncbi.nlm.nih.gov/pubmed/21943152 paper] also investigating the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
A [http://www.ncbi.nlm.nih.gov/pubmed/22906231 study] from August this year looked into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular part of the research looking to determine whether Neurog1 and Neurog2 were required for olfactory bulb development utilised a loss-of-function technique to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomernasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cryptorchidism:''' Failure of one or both testes to migrate into the scrotum during male foetus development.

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Gynaecomastia:''' The development of abnormal mammary glands in males characterised by enlarged breasts.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nystagmus:''' Refers to fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Pes cavus:''' A deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. Also referred to as clawfoot.

'''Spastic paraplegia:''' A hereditary paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.

'''Synkinesia:''' Refers to the ability to conduct voluntary movements, however, with accompanied involuntary muscular movements.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

----

{{2012Projects}}

2012 Group Project 4

2012-09-26T01:40:01Z

Z3374215: /* Diagnosis and Treatment */

=Olfaction Development=

== Introduction ==

WAKE UP AND SMELL THE ROSES! The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity.
Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants.
Odorants produce olfactory sensation at very low concentration,
and through the reaction with chemoreceptors enables the sense of smell in humans.
The olfactory system are often divide into a peripheral mechanism,
activated by an external stimulus and transforming it into an electric signal in neurons,
and a central mechanism where all signals formed by olfactory are integrated in the
central nervous system and processed to recognise odor.
Over 1000 genes which make up three percent of the total human genome which encode for
olfactory receptor types which can each detect a small number of related molecules and
respond with different level of intensity. It has been discovered that olfactory receptor
cells are highly specialized to particular odors.

This page seeks to explore the development of the olfactory system in addition to their function and physiology. This page will also examine both structural and neurological abnormalities that can arise. Within this page, current research is looked into, and analyzes the possible future research within the olfactory system.

== History of Discovery ==
{|
|-bgcolor="#65B1FF"
| width=10%|'''Year'''
| width=15%|'''Person'''
| width=75%|'''Contribution'''
|-
|'''1703'''
|'''Frederick Ruysch'''
| Discovery of [[#Glossary|Vomeronasal organ]] <ref name:"PMID12884838"><pubmed>12884838</pubmed></ref>
|- bgcolor="#CBE5FF"
|'''1856'''
|'''Maestre de San Juan'''
| The first person to link hypogonadism to the olfactory system<ref name="PMID16952059"><pubmed>16952059</pubmed></ref>
|-
|'''1891'''
|'''Von Kupffer'''
|Von Kupffer is recognised with description of the olfactory placodes as ectodermal thickenings<ref name:"PMID15836430"<pubmed>15836430</pubmed></ref>. For a time they were termed Kupffer placodes.
|-bgcolor="#CBE5FF"
|'''1899'''
|'''B.H. Buxton'''
| B. H. Buxton published a paper containing a series of photographs of a day 25 human embryo in the Journal of Anatomy and Physiology. He noted the thickened ridges of epiblast, the olfactory plates but there were at that stage no olfactory pits <ref name:”PMID17232381”><pubmed>17232381</pubmed></ref>.
|-
|'''1900s'''
|'''Julius Kollmann'''
| [[File:Nasal placode diagram.jpeg|thumb|right|250px|alt=Alt|Kollmann's diagram of developing nasal placode[http://embryology.med.unsw.edu.au/embryology/index.php?title=File:Kollmann671.jpg]]]

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology<ref name:"PMID3548583"><pubmed>3548583</pubmed></ref>. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of ectoderm<ref>Kollmanm, J. (1907). '''Atlas of the Development of Man''' (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page</ref>
|-bgcolor="#CBE5FF"
|'''1941'''
|'''Anthony A. Pearson'''
| Pearson conducted a study in examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the cribriform plate<ref>A A Pearson '''The Development of the Olfactory Nerve in Man''' J. Comp. Neurol.:1941, 75(2);199-217</ref>
|-
|'''1944'''
|'''Frank Kallmann'''
| Kallmann looked at three families who suffered from the now-called [[#Kallmann's Syndrome|Kallmann's Syndrome]]. Frank Kallmann was a genetist and psychiatrist. By analysing these familial groups he hypothesised about the inheritance of the disease<ref name="PMID16952059"/>
|-bgcolor="#CBE5FF"
|'''1954'''
|'''De Morsier'''
|De Morsier reported other patients suffering from similar symptoms to those reported by Kallmann (hypogonadism, anosmia, midline anatomic defect) but he termed the condition olfactogenital dysplasia suggesting a link between hypogonadism and the hypothalamus<ref name="PMID16952059"/>
|-
|'''2004'''
|'''Linda B. Buck'''
'''and Richard Axel'''
|Won the Nobel Prize in Physiology or Medicine for their work on the olfactory system<ref> "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Nobelprize.org. 27 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html</ref>
|}

== Anatomy of the Olfactory System ==

[[File:Olfactory_bulb_and_epithelium.png|200px|thumb|right|Cribiform plate and Olfactory Bulb/Epithelium]]

The nasal cavity is an important structure of the Olfactory system as within the turbinates or nasal conchae are found. These structures act to direct air inspired toward the olfactory epithelium.
The epithelium is located in the upper posterior region of the nasal cavity and is approximately a couple of centimeters wide. Olfactory epithelium is a specialized epithelium which contains around 100 million receptor cells. The olfactory epithelial cells is also the origin of olfactory vesicles which are known to contain kinocilia. The Olfactory vesicles are also known to serve in the process of stimulus transduction.

==== Olfactory Epithelium ====

[[File:Olfactory_epithelium.jpg|300px|thumb|right|Olfactory Epithelium]]

Olfactory epithelium consists of pseudostratified epithelium which contain olfactory receptors along with nerve cells whose axons attach to the olfactory bulb of the brain.

==== Olfactory Bulb ====

[[File:New olfactory bulb.jpg|300px|thumb|right|Olfactory Bulb]]

== Normal Function ==

===Olfactory Signal Transduction===
The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell.
<ref name="PMID21882432">[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction] Edited by Anna Menini. Boca Raton (FL): CRC Press; 2010. ISBN-13: 978-1-4200-7197-9</ref>

== Timeline of developmental process ==

{| cellpadding=5 style="border:1px solid #BBB"
|- bgcolor="#89CFF0"
|'''Week/Stage'''||Patterning Genes||Description||Image
|- bgcolor="#BCD4E6"
|''Week 4'' ||
Early expression of genes in the ''Hes5'' family suggests it's role in pre-patterning of the placode ectoderm.<ref name="PMID15893982"><pubmed>15893982</pubmed></ref>

Wnt, BMP, and FGF are known to play a role in the early migration of neural crest cells to the olfactory placode however the exact mechanisms of signalling are still uncertain.<ref name="PMID16093325"><pubmed>16093325</pubmed></ref>
||
All five facial swellings form initially surrounding the stomodeum.

The '''frontonasal prominence''' is the facial swelling which gives rise to '''olfactory placodes'''. It overlies the forebrain and arises from neural crest cells derived from midbrain and forebrain<ref name="PMID21882426"><pubmed>21882426</pubmed></ref>. An interesting study of neural crest cell migration in rats revealed that the origins of neural crest cells during frononasal development change in relation to the stage of somite development<ref name="PMID8045344"><pubmed>8045344</pubmed></ref>:

- 3 to 5 somite stage: lateral edge of the prosencephalon(forebrain) produced cells which migrated to the frontonasal mass while anterior neural ridge cells in the prosencephalon contributed to the nasal placode epithelium. mesencephalic region(midbrain) produced neural crest cells which contributed to the frontonasal mass.

- 5 to 10 somite stage: Anterior portion of the mesencephalon continued producing crest cells for migration to the frontonasal mass.

These cranial neural crest cells follow paths determined by prepatterned Sonic Hedgehog (SHh) signalling to the ventrolateral mesenchyme of the facial primordia. It has also been evident that nonneural crest components provide important signals during craniofacial patterning of the epithelium and mesodermal mesenchyme after migration and positioning. Proliferation and differentiation into the olfactory placodes occurs after positioning. <ref name="PMID12642481"><pubmed>12642481</pubmed></ref>

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.<ref name="PMID16677629"><pubmed>16677629</pubmed></ref>

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.<ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>
||
image
|- bgcolor="#89CFF0"
|''Week 5'' ||
Genes Involved
||

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

The lining of the olfactory placode thickens and differentiates into three layers within the pseudo-stratified organised epithelium:<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Inner basal layer''': composed of two cell types, the '''horizontal''' and '''globose''' basal cells.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Intermediate layer''': contains olfactory sensory neurons which ascend to the apical layer as they become more differentiated.<ref name="PMID438867"><pubmed>438867</pubmed></ref>

'''Apical layer''': contains the mature olfactory sensory neurons as well as the nuclei and bodies of the supporting '''sustentacular cells'''. <ref name="PMID438867"><pubmed>438867</pubmed></ref>

During the fetal period, the developing olfactory epithelium concentrates its mitotically active cells in the apical layer whilst post-natally these cells migrate to the inner basal layer.<ref name="PMID5558232"><pubmed>5558232</pubmed></ref>
At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated '''cribriform plate'''. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

Glial cells: Appear to originate in the olfactory placode compared to most Schwann cells, that they resemble, that originate from neural crest cells. Later, they migrate to the periphery of the olfactory nerve and later into the centre of the nerve.<ref name="PMID1281697"><pubmed>1281697</pubmed></ref> As olfactory nerve receptor neuron axons enter the olfactory bulb, the glial cells follow and distribute themselves along the edge of the olfactory nerve layer of the olfactory bulb in the central nervous system, as well as the olfactory nerve in the peripheral system.<ref name="PMID4069357"><pubmed>4069357</pubmed></ref> Olfactory nerve glial cells ensheath bundles of many small diameter olfactory nerve axons allowing close contact between olfactory nerve axons. <ref name="PMID1740543"><pubmed>1740543</pubmed></ref>

||
Image
|- bgcolor="#BCD4E6"
|''Week 6'' ||
Genes
||
The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages. <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
</ref>

'''Nasolacrimal groove''':This groove forms between the lateral nasal process and the adjacent maxillary prominence.

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.

'''Olfactory bulb''' growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere.
The synpasing cells differentiate to become the secondary sensory neurons, '''mitral cells''', of the olfactory pathways.

'''Olfactory nerve''' formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens.
As a result, the CNS olfactory tracts look stalk-like.
'''Olfactory nerve''': the '''olfactory tract''' and bulb together.
||
Image
|- bgcolor="#89CFF0"
|''Week 7''||
Genes
||
'''Nasolacrimal duct and sac''': The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla
After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity.

'''Intermaxillary process''': The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, '''Nasal fin.'''

'''Oronasal Membrane''': The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane

'''Primitive choana''': formed as the oronasal membrane ruptures.

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.

[[#Glossary |'''word linked to glossary''']]
||
Image
|- bgcolor="#BCD4E6"
|''Week 8''||
Genes
||
'''Nasal septum''' and '''philtrum''':Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline .
||
image

|}

EFFECT OF AMNIOTIC FLUID ON THE DEVELOPMENT OF OLFACTION IN THE FETUS still to be ncluded!

== Congenital Abnormalities ==

===Olfactory Defects===
Anosmia is defined as the absence of a sense of smell. Hyposmia refers to a reduced sense of smell. These conditions, when they occur as a congenital feature, can be associated with [[#Choanal Atresia|'''Choanal Atresia''']] or [[#Kallmann's Syndrome|'''Kallmann's Syndrome''']]. At present, these conditions are the most commonly recognised contributions to abnormal olfactory function.

===Choanal Atresia===

====Introduction and Epidemiology====
Choanal atresia is a congenital abnormality characterised by "narrowing of the posterior or complete obliteration of the nasal aperture" by a bony or membranous occlusion <ref name="PMID7876733"><pubmed>7876733</pubmed></ref><ref name="PMID8544637"><pubmed>8544637</pubmed></ref>. This anomaly occurs in 1 in every 7000 to 8000 births with a female predominance <ref name="PMID881923"><pubmed>881923</pubmed></ref>.
* 45% of cases are bilateral involving both choanae <ref name="PMID8544637"/>.
* Mixed bony and membranous anomalies were most common (70%) followed by pure bony atresia (30%) with no pure membranous anomalies<ref name="PMID8544637"/>.
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate. Ramsden <ref name="PMID19328897"><pubmed>19328897</pubmed></ref>notes that "A number of embryological models for the development of choanal atresia have been proposed, although none of them are wholly supported by convincing clinical evidence:
* Persistence of the buccopharyngeal membrane from the foregut <ref>Flake C.G., Ferguson C.F.: Congenital choanal atresia in infants and children. Ann Otol Rhino Laryngol 70. 1095-1110.1961</ref>
* Failure of perforation of the nasobuccal membrane of Hochstetter
* Abnormal persistence or location of mesoderm forming adhesions in the nasochoanal region
* Misdirection of neural crest cell migration" <ref name="PMID7098739"><pubmed>7098739</pubmed></ref>

===Kallmann's Syndrome===
====Introduction and Epidemiology====
Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic [[#Glossary |'''hypogonadism''']] characterized by a diminished or absent sense of smell <ref name="PMID22882983"><pubmed>22882983</pubmed></ref> <ref name="PMID6932275"><pubmed>6932275</pubmed></ref>. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people <ref name="PMID16952059 "><pubmed>16952059</pubmed></ref>, affecting males to females in a 5:1 ratio <ref name="PMID21682876"><pubmed>21682876</pubmed></ref>. [[#Glossary |'''Anosmia''']] or [[#Glossary |'''hyposmia''']] occurs as a results of impaired development of the olfactory bulbs and olfactory nerves <ref name="PMID21682876"/>. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait <ref name="PMID21682876"/>.

====Pathophysiology====
The olfactory bulb is the first neuronal checkpoint for olfactory information<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells <ref name="PMID12007408"/>. The axons of these neurons form the olfactory tract.

[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive<ref name="PMID21682876"/>. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome, though their functions are still being researched. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes <ref name="PMID20949504"><pubmed>20949504</pubmed></ref>:
* KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 and is expressed in the outer neuronal layers of the developing olfactory bulb. <ref name="PMID1913827"><pubmed>1913827</pubmed></ref>. Anosmin-1 stimulates lateral olfactory tract axon branching and outgrowth from OB towards the piriform cortex; this is through patterning of mitral and tufted cell axons to the olfactory cortex<ref name="PMID12007408"><pubmed>12007408</pubmed></ref>. Consequently, in its absence, Kallmann's syndrome arises due to abnormal olfactory neuronal development<ref name="PMID12007408"/>. Additionally, anosmin-1 has been shown to interact with FGFR1, explaining the digenic nature of Kallmann's syndrome<ref name="PMID20117945"><pubmed>20117945</pubmed></ref>.
* KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome<ref name="PMID20117945"/>. KAL2 encodes fibroblast growth factor receptor 1 involved in OB morphogenesis and GnRH neuronal development and migration<ref name="PMID20117945"/><ref name="PMID12627230"><pubmed>12627230</pubmed></ref>.
* FGF8: Encodes the key ligand for FGFR1. FGF binds with high affinity to FGFR and induces receptor activation.
* PROKR2: Encodes the G protein-coupled receptor prokineticin receptor-2 which is known to be involved in intracellular Ca2+ signalling<ref name="PMID18826963"><pubmed>18826963</pubmed></ref>. However, the exact role in Kallmann's syndrome has yet to be clarified<ref name="PMID18826963"/>. In terms of mode of inheritance, monoallelic PROKR2 mutations are not sufficient to produce the disease phenotype; it is hypothesised that digenic or oligogenic inheritance of KS in patients heterozygous for PROKR2 mutations produce the disease phenotype<ref name="PMID18826963"/>.
* PROK2: Encodes the PROKR2 ligand<ref name="PMID18826963"/>.

As a result of the OB structural abnormalities and neuronal migration failures, olfactory signals from the environment cannot be transmitted to the cerebral cortex. Additionally, the failure of the GnRH neuronal migration to the hypothalamus results in a loss of a key path in the negative feedback loop for sex hormone production.

====Clinical Features====

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)<ref name="PMID22882983"/>. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH <ref>Smith, N. (2008). ''Characteristics of Kallmann’s syndrome and HH''. Retrieved from http://kallmanns.org/node/96.</ref>. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype <ref name="PMID22882983"/>:

'''Reproductive Features'''
* [[#Glossary |'''Hypogonadotropism''']] leading to failed or arrested puberty <ref name="PMID16932275"><pubmed>16932275</pubmed></ref>
* [[#Glossary |'''Hypogonadism''']]
* [[#Glossary |'''Cryptorchidism''']] (males)
* [[#Glossary |'''Gynaecomastia''']] (males)
* Absence of menstruation, amennorhoea (femaleS)

'''Non-Reproductive Features'''
* Affected sense of smell: decreased (hyponosmia) or absent (anosmia) sense of smell <ref name="PMID16932275"/>. Anatomically, the olfactory bulbs and olfactory tracts demonstrate [[#Glossary |'''aplasia''']] or [[#Glossary |'''hypoplasia''']] <ref name="PMID16932275"/>.
* [[#Glossary |'''Eunuchoidism''']] bone structure, defined by long limbs as a result of inadequate calcification<ref>Smith, N. (2008). ''Euchanoid Pattern [in Kallmann's Syndrome]''. Retrieved from http://kallmanns.org/node/86.</ref>
* [[#Glossary |'''Unilateral renal aplasia''']] <ref name="PMID1080088"><pubmed>1080088</pubmed></ref>
* Cleft palate<ref name="PMID16932275"/>
* [[#Glossary |'''Pes cavus''']] <ref name="PMID16932275"/>
* Neurological symptoms
** [[#Glossary |'''Synkinesia''']]
** Abnormalities in eye movement
** [[#Glossary |'''Cerebellar ataxia''']]
** Evoked horizontal [[#Glossary |'''nystagmus''']]
** Sensorineural deafness
** Spatial attentional abnormalities
** [[#Glossary |'''Spastic paraplegia''']]
** Mental retardation <ref name="PMID16932275"/><ref name="PMID6881209"><pubmed>6881209</pubmed></ref> <ref name="PMID11531922"><pubmed>11531922</pubmed></ref> <ref name="PMID11297579"><pubmed>11297579</pubmed></ref>
===Diagnosis and Treatment===
{|class="wikitable collapsible collapsed"
|-
!Diagnosis and Treatment
|'''Diagnosis'''
Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism <ref name="PMID11052640"><pubmed>11052640</pubmed></ref>. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty <ref name="PMID11052640"/>. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours<ref name="PMID11052640"/>. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:
* Olfactory tests
* Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
* Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism <ref name="PMID20949504"/>
* Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion <ref name="PMID20949504"/>. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed <ref name="PMID20949504"/>
* Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome <ref name="PMID20949504"/>.
|-
|'''Treatment'''
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.
|}

====Treatment====
* Fertility treatment
* Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
* Treatment to prevent osteoporosis: HRT and vitamin D supplementation <ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/</ref>.

== Current Research ==

===Contribution of Neural Crest and Ectoderm to Nasal Placode===
A [http://www.ncbi.nlm.nih.gov/pubmed/21543621 paper]published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomeronasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as [[#Glossary |'''anosmia''']] and Kallmann syndrome<ref name:”PMID21543621”><pubmed>21543621</pubmed></ref>.

===Contribution of Cranial Neural Crest to Olfactory System===
[[File:Neural crest-derived cells in the embryonic olfactory epithelium.jpg|thumb|right|alt=Alt|'''Contribution of Cranial Neural Crest to Olfactory System''' - Neural crest-derived cells in the embryonic olfactory epithelium]]Another [http://www.ncbi.nlm.nih.gov/pubmed/21943152 paper] also investigating the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate<ref name:“PMID21943152”><pubmed>21943152</pubmed></ref>.

===Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes===
A [http://www.ncbi.nlm.nih.gov/pubmed/22906231 study] from August this year looked into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular part of the research looking to determine whether Neurog1 and Neurog2 were required for olfactory bulb development utilised a loss-of-function technique to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis<ref name:”PMID22906231”><pubmed>22906231</pubmed></ref>.

===Migratory Path of GnRH===
Another [http://www.ncbi.nlm.nih.gov/pubmed/22912413 paper]also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomernasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2<ref name:”PMID22912413”><pubmed>22912413</pubmed></ref>

===SEMA3A deletion and Kallmann syndrome===
A recent [http://www.ncbi.nlm.nih.gov/pubmed/22416012 study]<ref name="PMID22416012"><pubmed>22416012</pubmed></ref> published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for [[#Kallmann's Syndrome|'''Kallmann's syndrome''']](KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons<ref name="PMID22416012"/>. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant<ref name="PMID22416012"/>. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction<ref name="PMID22416012"/>.

===Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development===
A [http://www.ncbi.nlm.nih.gov/pubmed/22046273 study] by Erblich et al. <ref name="PMID22046273"><pubmed>22046273</pubmed></ref> sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.<ref name="PMID22046273"><pubmed>22046273</pubmed></ref>

===Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons===
When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)<ref name="PMID22581782"><pubmed>22581782</pubmed></ref>. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal<ref name="PMID22581782"/>. A [http://www.ncbi.nlm.nih.gov/pubmed/22581782 study]<ref name="PMID22581782"/> published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

== Glossary ==

'''Aplasia:''' Absent development of an organ or tissue.

'''Anosmia:''' Lack of smell.

'''Cerebellar ataxia:''' Reduced control over muscle coordination arising from defects or damage to the cerebellum.

'''Cryptorchidism:''' Failure of one or both testes to migrate into the scrotum during male foetus development.

'''Eunuchoidism:''' Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

'''Gynaecomastia:''' The development of abnormal mammary glands in males characterised by enlarged breasts.

'''Hypogonadism:''' A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

'''Hypogonadotropism:''' Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

'''Hypoplasia:'''Incomplete development of an organ or tissue.

'''Nystagmus:''' Refers to fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.

'''Olfactory bulb:''' The primary part of brain which processes olfactory information.

'''Olfactory epithelium:''' mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

'''Olfactory nerve cell:''' Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

'''Pheromone:''' Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

'''Pes cavus:''' A deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. Also referred to as clawfoot.

'''Spastic paraplegia:''' A hereditary paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.

'''Synkinesia:''' Refers to the ability to conduct voluntary movements, however, with accompanied involuntary muscular movements.

'''Vomeronasal Organ:''' To do with specific reproductive olfaction e.g. the detection of pheromones

== References ==
<references/>

==External Links==

[http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/ The Neural Basis of Olfaction]

[http://www.ncbi.nlm.nih.gov/books/NBK55972/ Development of the Olfactory System]

[http://neurondevelopment.org/olfactory-development The Development of the Olfactory System 2]

[http://www.leffingwell.com/olfaction.htm General Physiology of Olfaction]

[http://www.neuraldevelopment.com/content/3/1/33/ Neural Development]

[http://brain.utah.edu/research/wachowiak/index.php Olfactory Systems Laboratory]

[http://www.youtube.com/watch?v=fIFWt6WWYO0| Anatomy and Physiology of Olfaction]

[http://www.youtube.com/watch?v=uQ_qiqeD1Uo The Neurology of Smell ]

[http://www.ncbi.nlm.nih.gov/books/NBK55980/ The Neurobiology of Olfaction]

[http://science.howstuffworks.com/environmental/life/human-biology/smell2.htm Olfactory System]

{{External Links}}

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

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