Embryology - User contributions [en-gb]

User:Z3333038

2012-10-16T22:39:56Z

Z3333038: /* Lab Attendance */

==Individual Assessments==

===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 History of In Vitro Fertilisation====
In vitro fertilisation (IVF) refers to the process of artificial fertilisation conducted ex vivo. The IVF technique was first described for non-human use. The earliest known research conducted was by Walter Heape from Cambridge University in the 1890s who reported the first known case of embryo transplantation in rabbits. In 1959, Dr. Min Chueh Chang published his work in Nature describing the first successful mammalian live birth (rabbits) after IVF therapy.

Eventually, the use of IVF for humans became a possibility and then a reality: in 1978, the first successful birth from IVF occurred in England. The success of this IVF birth is credited to Patrick Steptoe and Robert Edwards. In 2010, Edwards was awarded the [http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/ Nobel Prize in Medicine] for the development of human IVF therapy. Because of IVF, many couples have been given a chance to conceive. However, the [http://www.ivf-worldwide.com/ivf-history.html/ history of IVF] is still in the making with constant improvements in the technology being developed and applied.

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

====Research in Fertilisation====

In order for fusion between mammalian gametes to occur, a spermatozoon must first pass through the external layers surrounding the oocyte: the cumulus oophorus and the zona pellucida (ZP). It is believe that the acromosome reaction (AR) of the spermatozoa starts upon contact with the zona pellucida. Consequently, the cumulus cell layer is typically removed in studies of mouse sperm-oocyte interactions in order to facilitate fertilisation. The recent experiments of Jin et al. <ref name="PMID21383182"><pubmed>21383182</pubmed></ref> sought to answer the question: "Where does the fertilising mouse spermatozoon begin the AR - in the cumulus [of the oocyte] or the zona pellucida?" Jin et al. <ref name="PMID21383182"/> utilised fluorescence microscopy and transgenic mouse spermatozoa to conduct their investigation. Additionally, Jin et al. <ref name="PMID21383182"/> used cumulus-free oocytes and cumulus-enclosed oocytes to study the role of the cumulus cells in fertilisation.

From the experiment, Jin et al. <ref name="PMID21383182"/> found that most fertilising spermatozoa begin the AR before their first contact with the ZP. The significance of this finding was that the spermatozoa with intact acromosomes at the ZP seldom had the ability to penetrate through <ref name="PMID21383182"/>. In contrast, spermatozoa which had already began the AR could easily penetrate the ZP. In regards to the role of the cumulus cells, it was found that cumulus-enclosed oocytes had a higher incidence of fertilisation compared to cumulus-free oocytes <ref name="PMID21383182"/>. Moreover, cumulus-free oocytes had an increased incidence of in vitro fertilisation when incubated with other cumulus-enclosed cells; this finding suggests that cumulus cells harbour an important role in fertilisation <ref name="PMID21383182"/>. However, it is notable that when cumulus-free oocytes were incubated in a cumulus-conditioned medium, no increase in fertilisation rate was noted<ref name="PMID21383182"/>. Overall, two conclusions were made: firstly, that the AR is required by the spermatozoa prior to meeting the ZP for effective fertilisation<ref name="PMID21383182"/>. Secondly, the cumulus oophorus confers benefit in increasing the chance of fertilisation<ref name="PMID21383182"/>.

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 16:58, 11 September 2012 (EST) Question 1 is answered well and linked to appropriate resources. Question 2 is also quite a complete answer to what I requested. The formatting of your description could have been better organised, while it is correct to cite the paper when referring to the findings, this is a little overboard with 9 times within 2 paragraphs. If you had organised the information differently this could have been reduced to 1-2 citations within the text. Alternatively the findings could have been provided as a bullet or numbered list. '''10/10'''

===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.''
====Patterns of ZPC Deposition in Porcine Oocyte-Cumulus Complexes====
[[File:Patterns_of_ZPC_Deposition_in_Porcine_Oocytes.jpg‎]]

Immunofluorescence Detection for ZPC and Ubiquitin in a Porcine Oocyte <ref name="PMID21383844"><pubmed>21383844</pubmed></ref>

'''References'''
<references/>

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

Trophinin is a membrane protein expressed in chorionic villi trophoblasts and in the maternal endometrium. In the early stages of pregnancy, trophinin is strongly expressed along with tastin and bystin, which form a complex; this complex mediates apical cell adhesion between the trophoblasts and the endometrial epithelial cells<ref name="PMID14633596"><pubmed>14633596</pubmed></ref>. The time frame in which trophinin is expressed on the apical aspect of the endometrial cells coincides with the "implantation window"<ref name="PMID14633596"/>; the period in which successful implantation is possible. Trophonin-trophonin adhesion during implantation occurs via signal transduction with bystin and tastin<ref name="PMID22201876"><pubmed>22201876</pubmed></ref>. As a consequence of trophinin-trophinin adhesion, trophectoderm cells become activated for implantation<ref name="PMID22201876"/>. Moreover, there have been reports that endometrial epithelial cells undergo apoptosis upon blastocyst adhesion; human trophoectoderm cells express the Fas ligand which interacts with Fas expressed on the endometrium<ref name="PMID22201876"/>. However, other studies have shown that trophinin-mediated cell adhesion can induce endometrial cell apoptosis through mechanisms other than the Fas/FasL cascade<ref name="PMID22201876"/>.

In regards to ectopic pregnancies located within the fallopian tube, research has shown that trophinin is strongly expressed by both the embryonic trophoblasts and maternal fallopian tube epithelium, induced by human chorionic gonadotrophin (hCG)<ref name="PMID14633596"/>. These findings highlight the function of trophonin in facilitating implantation in conjunction with its role in the pathogenesis of ectopic pregnancies.

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 17:04, 11 September 2012 (EST) Question 1 image has been correctly uploaded and contains all the requested information in the summary box. Question 2 is a good description of this recent paper on trophinin and Implantation. '''10/10'''

===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.''
====Gestational Age versus Post-Fertilisation Age====

Gestation is the period of time between conception and birth (Kaneshiro, 2011; Vishton, 2011). Gestational age is the developmental age of the conceptus based on the presumed first day of the last normal menstrual period to the current date, measured in weeks (Kaneshiro, 2011; Vishton, 2011). In contrast, post-fertilisation age refers to the age of the conceptus expressed in elapsed time since fertilisation (Vishton, 2011). Gestational age is approximately two weeks greater than post-fertilization age (Kaneshiro, 2011; Vishton, 2011). Gestational age is used in human development because its start date can be determined by asking the mother when was the presumed first day of the last normal menstrual period (Kaneshiro, 2011; Vishton, 2011). In contrast, the moment of fertilization must be inferred (Vishton, 2011).

'''References'''

Kaneshiro, N. K. (2011). ''Gestational age''. Retrieved from http://www.umm.edu/ency/article/002367.htm

Vishton, P. M. (2011). ''Embryo Foetus Development Stages''. Retrieved from http://www.livestrong.com/article/92683-embryo-fetus-development-stages/

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

====Tissues Derived From Somites====

'''1. Bone (Sclerotome)'''

Bone tissue consists of cells separated by an extracellular matrix with organic and inorganic components (Marieb, Wilhem & Mallatt, 2010). The organic components of bone consists of cells, collagen fibres and ground substance. The cells include osteoprogenitor cells which give rise to osteoblasts: the producers of new bone matrix (osteoid). Mature osteoblasts, called osteocytes, are trapped in lacunae where they maintain the mature bone; osteocytes may revert to osteoblasts in the incidence of a fracture. Osteoclasts are multinucleated cells with ruffled plasma membrane borders and are involved in bone resorption. Bone resorption is important for bone remodelling to improve tensile strength as well as remodel the newly deposited woven bone into mature bone after a fracture. There are two types of mature (lamellar) bone: compact bone and spongy bone (Marieb et al., 2010). The compact bone occurs towards the periphery and is arranged in Haversian systems: lamellae concentrically arranged around a central Haversian canal containing blood vessels, nerves and osteocytes (Marieb et al., 2010). The different Haversian systems communicate with each other, the periosteum and endosteum through the Volkmann's canals. In contrast, spongy bone in the mature adult appears towards the centre of the diaphysis and metaphysis and is arranged in bony shelves (trabeculae) (Marieb et al., 2010). The gross porous arrangement of spongy bone is important for housing the bone marrow (Marieb et al., 2010)

'''2. The Skin (Dermotome)'''

a. ''Dermis'': The dermis is made up of two main regions: (1) the superficial papillary layer and (2) the deeper reticular layer (Marieb et al., 2010). The superficial papillary layer makes up 20% of the dermis and is areolar connective tissue consisting of collagen and elastic fibres; it includes the dermal papillae which extend into the overlying epidermis to strengthen the dermal-epidermal junction and increase surface area for nutrient, gas and waste exchange with the avascular epidermis (Marieb et al., 2010). The reticular layer is composed of dense irregular connective tissue with thick bundles of collagen and elastic fibres arranged in different planes (Marieb et al., 2010). Other cells interspersed among the connective tissue of the dermis include fibroblasts, macrophages, mast cells and other white blood cells including lymphocytes(Marieb et al., 2010). The dermis is highly vascular and supplied with nerve fibres (Marieb et al., 2010). There are two vascular plexuses; the deep dermal plexus and the subpapillary plexus (Marieb et al., 2010). These vessels serve not only for nutrient supply to the dermis and epidermis, but for temperature regulation as well (Marieb et al., 2010).

b. ''Hypodermis'': The subcutaneous layer, or fatty hypodermis, consists of areolar and adipose connective tissue(Marieb et al., 2010). The cellular components include adipocytes as well as white blood cells (Marieb et al., 2010). The hypodermis serves to store fat and anchor the skin to underlying structure in a manner that the skin can slide over structures(Marieb et al., 2010). Additionally, the adipose in the hypodermis serves an insulator.

'''3. Skeletal Muscle (Myotome)'''
Skeletal muscle fibres come together to form a larger skeletal muscle surrounded by different levels of connective tissue "coats": the epimysium surrounds the whole skeletal muscle, the perimysium covers each fascicle and the loose CT endomysium separates each skeletal muscle fibre (Marieb et al., 2010). The skeletal muscle fibres are long cylindrical cells with a diameter between 10-100um (Marieb et al., 2010) . These muscle fbres are formed by the fusion of embryonic cells and hence contain many nuclei which are located at the periphery of each fibre beneath the sarcolemma, the skeletal muscle cell membrane (Marieb et al., 2010). These muscle fibres appear striated because of the internal organelles of the muscle fibres: myofibrils, the contractile organelles of muscle tissue (Marieb et al., 2010).

'''References'''

Marieb, E. N., Wilhelm, P. B., Mallatt, J. (2010). ''Human Anatomy'' (6th ed.). San Francisco, CA: Pearson Education, Inc.

--[[User:Z8600021|Mark Hill]] 17:10, 11 September 2012 (EST) Question 1 Clearly identified and cited the difference between "gestational age" and "post-fertilisation age". Question 2 you have also identified histological descriptions at least 3 different types of tissues formed from somites. For both questions you could have formatted the references and the reference list by using the <nowiki><ref></ref></nowiki> tags and simply inserted any text that you wanted in your list between the tags. '''10/10'''

===Lab 4 Assessment===

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

*'''Amniocentesis''' <ref>Moore, K. L., Persaud, T. V. N. & Torchia, M. G. (2013). ''The Developing Human'' (9th ed.). Philadelphia, PA: Elsevier Saunders. </ref>: Amniocentesis refers to sampling of the amniotic fluid by inserting a needle through the mother's anterior abdominal and uterine walls into the amniotic cavity by piercing the chorion and amnion. This technique is performed at 15 and 18 weeks gestation. Amniocentesis is often used to detect genetic disorders as it allows for chromosome analysis. One abnormality which can be detected is trisomy 21 (Down's Syndrome)[1]. Additionally, amniocentesis can be utilised for alpha-fetoprotein assays to detect neural tube defects like spina bifida [1].

*'''Chorionic Villus Sampling''' [1]: Biopsies of trophoblastic tissue are obtained by inserting a needle through the mother's abdominal wall and uterine walls to the uterine cavity. Sampling can also be performed through the cervix with a polyethylene catheter, guided by real-time ultrasonography. CVS can be performed sooner than amniocentesis at 10 and 12 weeks of gestation. However, the rate of miscarriage from CVS is higher than amniocentesis. Like amniocentesis, CVS can be used to detect chromosomal abnormalities like trisomy 21 as well as trisomy 18. Additionally, Tay-Sachs disease can be detected with CVS [1].

====The Therapeutic Use of Cord Stem Cells====
''2. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.''

Fu et al. (2006) sought to isolate human umbilical cord mesenchymal stem cells (HUCMSCs) and transform them into dopaminergic neurons in vitro <ref name="PMID16099997"><pubmed>16099997</pubmed></ref>. The experiment was carried out in the interest of finding a potential cure for Parkinson's disease from HUCMSCs [2]. The procedure involved isolating human mesenchymal stem cells from Wharton's jelly of the umbilical cord and culturing the HUCMSCs in a neuronal conditioned medium (NCM) [2]. The differentiation of the HUCMSCs into dopaminergic neurons was induced through stepwise culturing with the NCM, sonic hedgehog and FGF-8 [2]. The successfully transformed HUCMSCs into dopaminergic neurons were selected by positive immunohistochemistry staining for tyrosine hydroxylase (TH), the rate-limiting catecholaminergic synthesizing enzyme, and dopamine secretion [2]. These neurons were then transplanted into the striatum of rats with induced Parkinson's disease by unilateral striatal lesioning with neurotoxin (6-hydroxydopamine hydrogen chloride)[2]. The effects of stem cell transplantation were examined in the Parkinsonian animals by quantification of rotations in the mice in response to amphetamine at 0, 1, 2, 3 and 4 months [2].

Despite a success rate of 12.7% of transformed HUCMSCs, the study found that the original number of HUCMSCs doubled after 3 days of culture [2]. Additionally, the transformed HUCMSCs were still viable in the rats 4 months post-transplantation without the need for immunosuppression [2]. These findings highlight HUCMSCs as a potentially safe source of organs due to their viability post-surgery and the lack of a negative host response to the newly transplanted tissues. Additionally, positive TH staining showed migration of the transformed HUCMSCs rostrally and caudally from the location of implantation [2]. Hence, the transformed HUMSCs were able to integrate properly into the patient (Parkinsonian mouse), putting forth their suitability as a tissue source for transplantation.

The clinical effects of the HUCMSCs on the Parkinsonian mice were assessed by comparing test subjects to two control groups. The first control group consisted of normal, non-Parkinsonian mice with a low score of rotation in response to amphetamine. The second control group contained Parkinsonian mice which received no treatment and had a high rotation score [2]. It was found that the second control group showed no improvement in rotation score and deteriorated further over time. Similarly, mice treated with non-transformed HUCMSCs did not have observable improvements and had a similar deteriorating rotation score to the untreated Parkinsonian animals [2]. This finding highlights that untransformed HUCMSCs confer no clinical benefit in the setting of simulated Parkinson's disease [2]. The Parkinsonian mice treated with transformed HUCMSCs at first had no observable improvement but over time showed significantly improved rotational scores relative to the Parkinsonian control group [2]. However, the transformed HUCMSCs group did not show improvement to the extent of returning to a normal level (non-Parkinsonian rat). These findings suggest that HUCMSCs could be a potential stem cell source for transplantation, however, the procedures for HUMSCs transformation and transplantation must first be reviewed [2]. Fu et al. (2006) suggested that, the number of dopaminergic neurons of implanted cells may have been relatively inadequate to alleviate the Parkinsonism symptoms in the affected rats. Additionally, the transplanted cells may take time to integrate into the host brain: only two rats in the transformed HUCMSCs group survived for at least 8 months, with amphetamine-induced rotation behavior remaining similar to that 4 months after transplantation. Hence, in order to properly assess HUCMSCs to treat Parkinson's disease, the long-term effects of transplantation must be studied [2].

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 17:18, 11 September 2012 (EST) Question 1 well answered in terms of technique and specific abnormalities. Question 2 human umbilical cord mesenchymal stem cells in Wharton's jelly have been used in several studies as potential sources of therapeutic cells. Perhaps a more recent paper next time. '''10/10'''

===Lab 7 Assessment===

====Muscle Satellite Cells====

''1. (a) Provide a one sentence definition of a muscle satellite cell''

Satellite cells are quiescent cells located beneath the basal lamina of each myofibre and function as myogenic precursors (stem cells) for postnatal muscle growth and repair <ref name="PMID16051152"><pubmed>16051152</pubmed></ref>.

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

Muscle satellite cells are at rest (G0) when skeletal muscle is not active<ref name="PMID22649641"><pubmed>22649641</pubmed></ref>. Activation can occur in the settings of physical activity and mechanical trauma <ref name="PMID12892408"/>. When satellite cells are activated, they proliferate and are converted to myoblasts which further differentiate and fuse with existing muscle fibres or form new fibres <ref name="PMID12892408"><pubmed>12892408</pubmed></ref>. The myonuclei accumulated in the tissue are of key importance for myogenesis: they aid in increasing protein synthesis and enable muscle growth (hypertrophy and hyperplasia) and regeneration<ref name="PMID16051152"/>. Without satellite cells, mature muscle fibres are unable to undergo regeneration <ref name="PMID16051152"/>. There is much speculation as to the exact mechanisms and factors which activate muscle satellite cells. It is proposed that strenuous exercise, mechanical muscle injury or myodegenerative disease result in the inflammatory response which recruits neutrophils and macrophages to the area of damage; the inflammatory mediators released in conjunction with growth factors secreted by the myofibres promote myosatellite activation <ref name="PMID12892408"/>. One proposed "triggering agent" is the production of sphingosine-1-phosphate from the inner part of the plasma membrane leading to satellite cell entry into the cell cycle <ref name="PMID17996437"><pubmed>17996437</pubmed></ref>. Additionally, mechanical stretch to the muscle fibre has been shown to trigger intracellular signals, such as nitric oxide synthesis which results in hepatocyte growth factor (HGF) release <ref name="PMID17996437"/>. Nitric oxide also induces follistatin, a fusigenic secreted molecule, which is an antagonist to myostatin. Myostatin is expressed by quiescent satellite cells and exerts a negative effect on satellite cell activation <ref name="PMID17996437"/>. IGF-IEa and MGF have also been implicated in satellite cell activation: Hill et al. (2003) demonstrated that these mediators are produced by active muscle in rodents and appear to be positive regulators of muscle hypertrophy<ref name="PMID12892408"><pubmed>12892408</pubmed></ref>. However, whilst MGF is acutely induced and is said to precede satellite cell activation, IGF-IEa has a delayed effect involved in the later phase of regeneration<ref name="PMID12892408"/>. Interestingly, in dystrophic muscles MGF is not produced, suggesting the importance of effective muscle repair to avoid the pathogenesis of muscular dystrophy syndromes <ref name="PMID12892408"/>.

Once activated, the satellite cells migrate out of the basal lamina and enter the cell cycle with coexpression of Pax7 and MyoD <ref name="PMID17996437"/>. This process occurs in conjunction with the Notch signaling pathway<ref name="PMID22493066"><pubmed>22493066</pubmed></ref>. The skeletal myoblasts that are produced divide, express myogenin and downregulate Pax7 then fuse to form myofibres<ref name="PMID17996437"/>.

====The Effects of Motor Nerve Damage on Skeletal Muscle====

''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?''

Chronic spinal cord injury (SCI) affects muscles below the level of the lesion. In terms of fibre type, one review <ref name="PMID19705475"><pubmed>19705475</pubmed></ref>describes the progressive change in fibre type toward faster phenotypes. The fibre phenotype is classified according to its myosin heavy chain (MHC) molecule which is an actin-based motor protein associated with muscle fibre contraction<ref name="PMID19705475"/>. These three MHC isoforms are MHC I, MHC IIa, and MHC IIx <ref name="PMID19705475"/>. In SCI there is a reduction of type I fibres (slow) and upregulation of type IIA and IIX fibres (fast)<ref name="PMID19705475"/>. The metabolism of the fast fibres is characterised by a predominantly anaerobic metabolism with fewer mitochondria, unlike type I fibres which undergo aerobic metabolism <ref name="PMID19705475"/>. This is in part due to a reduction in absolute activities of the muscle metabolic enzymes in SCI, favouring the fast glycolytic/oxidative type which fatigue more easily <ref name="PMID19705475"/>.

In terms of fibre size, a study by Castro et al. (1998) <ref name="PMID9887150"><pubmed>9887150</pubmed></ref> found that all fibre types underwent significant atrophy and decreased in size from the 6th to 24th week after injury<ref name="PMID9887150"/>. Moreover, average fibre cross-sectional area decreased by 22% by the 6th week post-injury <ref name="PMID9887150"/>. The changes were accompanied by either complete paralysis or loss of force with increased susceptibility to fatigue depending on the extent of injury <ref name="PMID9887150"/>. Note that whilst type II fibre atrophy is seen during the first months after complete SCI, type I fibres undergo atrophy in the later stages <ref name="PMID19705475"><pubmed>19705475</pubmed></ref>.

Interestingly, the level of the motor neuron lesion can affect the outcome of the muscle atrophy: a study by Stilwill and Sagha <ref name="PMID66912"><pubmed>66912</pubmed></ref>found that lower motor neuron lesions led to muscle fibre grouped atrophy and fibre-type grouping, whereas upper motor neuron lesions led to preferential atrophy of type II fibers with fibre-type grouping.

'''References'''
<references/>

===Lab 8 Assessment===
1. Each student should now look at each of the other Group projects in the class.

2. Next prepare a critical assessment (should include both positive and negative issues) of each project using the project assessment criteria.

3. This assessment should be pasted without signature on the top of the specific project's discussion page. (minimum length 3-5 paragraphs/project)

4. This critical assessment should also be pasted on your own student page. Each student should therefore have 5 separate reports pasted on their own page for this assessment item. Length, quality and accuracy of your reports will be part of the overall mark for this assessment (there will be a greater loading on this than simple question assessments).

====Vision====
In regards to the information presented (outcomes 1 and 9), as the project is still in progress it is understandable that some areas are incomplete. There is so far good, concise information on the structure of the development of the eye and the structures involved in vision. It would be useful to include information on the genetic factors involved in vision development as well as have a section explaining the processes involved with vision. Also, for the Current Research section (outcome 5), it would be better to explain the aims and findings of the research papers cited rather than just referencing the papers and images without describing their significance to research progress. In terms of peer teaching (outcome 4), the page contains a good balance between technical terms and simple language for understanding on the development of structures for vision; additionally, the inclusion Glossary helps to clarify any technical terms.

The most striking part of the layout (outcome 2) is the use of images to demonstrate the development of structures involved in vision. This is great because it makes the page interesting and provides a visual understanding on the development of the eye. However, at times the images could be better placed: for example, in the introduction the pictures appear stacked on top of one another. Additionally, the images in the introduction show similar structures, so perhaps select only one to better aid the flow and appearance of the page. Throughout the page, the images utilised could be provided with more description and linked to the text in order to improve flow and enhance written explanation. Perhaps some information, such as the timeline, could be sorted into a table to improve the layout.

In regards to outcome 3, some of the information provided (e.g. in the section on Development) is not referenced. Additionally, some of the references in the Reference list need to be formatted correctly with author, date, title of the page, publisher (if required) and any other necessary information. It would be useful to follow the style of the automatic default referencing.
Hope the feedback helps and all the best with your project!

====Somatosensory====
The introduction is good in that there is a description of the role of somatosensory functions as well as an overview of its development. To improve further, perhaps avoid trailing off in the final sentence and perhaps put something that concludes your introduction.

In regards to the information presented and layout (outcomes 1, 2, 4 and 9), the history of discoveries is very brief and requires more research. Additionally, it would be useful to set up a timeline to add interest. The section on the central somatosensory differentiation appeared very well researched with a very interesting picture to accompany the text – good work. The section on Touch would better be placed in a table and have accompanying images to avoid getting too ‘wordy’. Also, this section does not have any consistent referencing in the bulk of the content – please cite where you find your information. The section on pain is well researched and has a strong content, however, to enhance this section I would suggest using dot points to describe the different fibres and add a relevant image. Similarly, the hot/cold and pressure sections were great in terms of content but could use with some dot points and visual explanation to make the page more interesting. Just a note on pressure – avoid getting repetitive; the page had already defined the Ruffini’s endings/corpuscles etc in the section of Touch. Additionally, the 2 urls at the bottom of this section are distracting, make sure to incorporate these in your reference list of add them to an ‘External Links’ section. Your Current Research section requires some proof reading and additional articles to make it more comprehensive. However, you have referenced the image well and referred to it in the accompanying text.

In terms of referencing, I noticed some areas where the in-text references were not correctly formatted and were in the (Author, date) style. Perhaps have a look at the referencing tutorial on the Embryology ‘Students’ page to get an understanding of the codes required for citations. For peer teaching (outcome 4), make sure that you define all technical terms – your Glossary only has 2 definitions provided. Other than this, the content overall is interesting to read just make sure you are striking a balance between images and text. Hope it helps and all the best!

====Taste====

In regards to the information presented (outcomes 1 and 9), the timeline for the development is good and written with clarity. However, I noticed the section on structure only referred to the adult state rather than focusing on the embryonic origin of each structure (ectoderm, endoderm and mesoderm). I would suggest that you elaborate on the developmental stages introduced in the timeline in order to build on the information you have already provided. This is important in regards to outcome 6 so that you can relate your research to embryology – the development of taste should be your focus. The history timeline was great to read as it was very concise and clear.

The page shows a good level of peer teaching with clear language and a good balance between images and text (outcome 4) with technical terms explained in the glossary. An improvement could be to make a link between any technical language and the glossary to avoid scrolling up and down to the page. Your Current Research section (outcome 5) was very interesting to read and showed you went beyond the scope of basic research on taste – good work!

In terms of layout (outcome 2), whilst the images are interesting and relevant to the text, some are not appropriately referenced nor described; make sure to reference appropriately and at least write one or two sentences to make the images relevant to the reader. Additionally, the introduction should not be under another subheading (Gustatory system) as it creates some confusion; I would suggest making the introduction its own heading in order to make the page flow. Similarly, the history timeline would best be placed towards the beginning of the page, under the introduction.

I noticed some areas (such as the section on Structure) were not appropriately or consistently referenced. Make sure to include a citation anytime you introduce a researched idea or information to avoid being accused of plagiarism. I noticed the history timeline had good consistent referencing; however the numbers just need to be formatted so they come under the reference list. If you click on the Tutorial: References page linked from the student page, it tells you how to do this. Hope the feedback helps and all the best for your project!

====Abnormal Vision====
"The introduction is good in the manner that it provides some brief background information regarding the normal development of the eye and abnormalities. Additionally, I liked how the introduction described the aims of the page because it sets up a structure for the reader to follow. Just make sure to proof read this section: “The development of the eye is very sensitive and REQUIRES accurate...”

In regards to the information presented and layout (outcomes 1, 2, 4 and 9):

1. Normal Eye Development: This section appears very well researched. I like how you referred to the stages throughout development. However, this section could be enhanced by adding an image of the normal eye structure and development – this acts as a reference point for your page viewers, allowing for a clear visual comparison between the abnormalities and normal structure.

2. Abnormal Development: I like the overview provided at the beginning as it sets the scene for what points you will be covering in this section. Great job. All sections are quite good, just perhaps include more images to further enhance your page.

a. Abnormal lens development: I liked how you first described the function of the gene in development and then stated any abnormalities that arise when the gene is not expressed or mutated. I liked how you included an image for the crystalline genes; just make sure to refer to the image in text (e.g. see fig. 1. or see accompanying image).

b. Abnormal corneal development: Similar to the abnormal lens section, there is a good explanation provided for each gene involved. Just some improvements: make sure to reference all information; e.g. No reference provided for “The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of....”. The accompanying image has been referenced correctly and described, good work!

c. Abnormal retinal development: Once again, a great scope of research and information and suitable image. I liked how you described the impact of each mutation explicitly such as in Albinism “ganglion cells of retina decreased by 25%”. This really helps the reader to understand the extent of the abnormalities from certain gene mutations.

3. Ocular manifestations: the opening sentence is slightly vague. Could you please state which two separate sections that you are referring to? The section that follows could be better organised. It seems to jump from genetic issues to a research timeline then to future research on that disease to another example of a genetic mutation which produces abnormalities. I would suggest putting the research timeline shortly after the introduction and integrating research history not just on LCA but other abnormalities as well. However, the content for all these sections is well referenced and interesting to read. The balance between text and images between LCA and anopthalmia/micropthalmia sections is good and are both really interesting to read! I liked how you provided some epidemiological data and clinical manifestations in depth accompanied by suitable images. However, the environmental abnormalities section could use with more dot-point styles and images to enhance the presentation and aid in your descriptions.

In regards to peer teaching (outcome 5), this page was an absolute joy to read and all technical language was explained in the glossary. Just make sure to pay attention to those minor improvements. Good job!"

====Hearing====

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

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

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

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

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

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

===Lab 9 Assessment===

====Embryonic Blood Flow and Oxygen and the Developing Pancreas====

''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.''

A study by Shah et al.<ref name="PMID21050843"><pubmed>21050843</pubmed></ref> sought to investigate whether enhanced blood flow and oxygen in a developing mouse pancreas correlates with changes in differentiation during embryonic pancreatic development. This investigation was prompted because "there is a fundamental lack of understanding of how organs in early mammalian embryos are able to form despite receiving little or no blood flow" according to Shah et al.

The methods involved injecting fluorescein-conjugated tomato lectin (a vascular tracer) into the hearts of developing mouse embryos ''in utero'' at different stages of development, guided by ultrasound backscatter microscopy. The vascular tracer was left to circulate for 10 minutes and then the mice embryos were harvested for analysis of blood flow and oxygenation. One key finding discovered through immunohistochemistry was that the developing pancreas had dense vascularity, though numerous vessels early in gestation were non-perfused. Vessels that were not perfused with blood did not induce differentiation of adjacent pancreatic epithelium. In contrast, vessels perfused with blood were surrounded by glucagon-positive and insulin-positive cells; these are indications of pancreatic cell differentiation. However, ''in vitro'' it was found that the hypoxic embryonic pancreas shows proliferation but not differentiation. Interestingly, the endocrine areas tended to be areas with flow and higher oxygenation compared to the exocrine areas of the pancreas. Moreover, later embryonic stages when global pancreatic perfusion occurred correlated with a rapid increase in exocrine differentiation. Overall, Shah et al. concluded that vascular flow with oxygenated blood, as opposed to just vascular endothelium alone, may provide specific signals for pancreatic differentiation in the early embryo.

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

Through the interaction between the neural crest and the ectoderm, 10 teeth buds form in the the embryo on in the early embryo<ref>Universities of Fribourg, Lausanne and Bern. (2012). ''Development of the Teeth''. Retrieved from http://www.embryology.ch/anglais/sdigestive/gesicht05.html</ref>. Each tooth bud has an outer area of ectodermal orgign (the enamel organ) with an inner area of dental pulp made up of solidified mesenchyme of neuroectodermal origin. The neuroectodermal mesenchyme also forms the dental follicle from which the periodontium and cement of the tooth root arise.

* '''Ectoderm''' of the oral cavity produces:
** Ameloblasts which produce the teeth enamel in the direction of the tooth pulp.
* Surrounding '''mesoderm''' (mesenchyme) in conjunction with '''neural crest''' produces:
** Odontoblasts excrete predentin below the ameloblast layer; dentin then arises through calcium salt deposition in the predentin.
** Cementoblasts in the root of the tooth produce cement.

'''References'''
<references/>

===Lab 11 Assessment===

''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.''

The CCCTC-binding factor, CTCF, has been shown in the past to be involved in transcriptional control and chromatin interactions within the cell’s nucleus<ref name="PMID20020479"><pubmed>20020479</pubmed></ref>. A recent study by Hiroseu et al. <ref name="PMID22340434"><pubmed>22340434</pubmed></ref> sought to analyse the role of CTCF in induced pluripotent stem cells (iPS) by examining three cell lines: iPS cells induced from fibroblasts (201B7), human diploid fibroblasts (IMR90) and IMR90 cells undergoing oncongene-induced senescence (OIS) after Ras activation.

Hiroseu et al. noticed that CTCF mRNA was up-regulated in the iPS cells and down-regulated in the OIS cells in comparison to the IMR90 cells<ref name="PMID22340434"/>. Similarly, high levels of CTCF protein were expressed in the iPS cells whilst the OIS cells showed little CTCF protein expression <ref name="PMID22340434"/>. In order to clarify these results, Hiroseu et al. studied the interaction between CTCF and the and the INK4/ARF locus which encodes p15INK4b, p16INK4a and ARF: reprogramming regulators in the cell cycle which induce senescence<ref name="PMID19668188"><pubmed>19668188</pubmed></ref>. Using genome wide assay as well as CTCF binding profiles from data from past experiments, Hiroseu et al. where able to identify three CTCF enriched sites in the INK4/ARF locus: IC1, IC2 and IC3<ref name="PMID22340434"/>. These findings are significant as they suggest a relationship between CTCF function and INK4/ARF transcription.

Chromatin precipitation showed that CTCF could bind to IC1, IC2 and IC3 in all three cell lines<ref name="PMID22340434"/>. The affinity of CTCF binding was found to be significantly high in the iPS cells compared to IMR90 cells<ref name="PMID22340434"/>. Additionally, chromosome conformation capture assay showed that in both the iPS cells and IMR90 cells, p15INK4b, p16INK4a and ARF were silenced<ref name="PMID22340434"/>. In contrast, the OIS cells showed weak CTCF binding with increased expression of p15INK4b and p16INK4a<ref name="PMID22340434"/>. Data analysis uncovered that the inverse relationships of expression are a result of the interaction between the CTCF enriched sites and the , p15INK4b, p16INK4a and ARF promoters<ref name="PMID22340434"/>. IC1 and IC2 strongly interacted with the p15INK4b and ARF promoters respectively<ref name="PMID22340434"/>. Moreovereover, the IC1/ p15INK4band IC2/ARF “binding site-promoter complexes”, the p16INK4a promoter and IC3 were found to be colocalised in the nucleus; Hiroseu et al. suggested that these gene interactions involve the formation of chromosome loops in the INK4/ARG locus<ref name="PMID22340434"/>. This hypothesis was supported by CTCF knockdown which was found to decrease the colocalisation of the genes, leading to a looser chromatin formation; this was coupled with increased expression of p15INK4b, p16INK4a <ref name="PMID22340434"/>. From these findings, Hiroeu et al. drew the conclusion that the CTCF complex is important for compact chromatin formation at the INK4/ARF locus<ref name="PMID22340434"/>.

In OIS cells, chromatin was found to undergo active decompaction which was related to its senescence as it allowed the expression of p15INK4b and p16INK4a<ref name="PMID22340434"/>. In contast, repressive compaction and intermediate compaction was demonstrated in the IMR90 and iPS cells respectively, explaining the silencing of the genes in the INK4/ARF locus<ref name="PMID22340434"/>. The implications of these findings for iPS research are two fold. Firstly, that CTCF is crucial for higher-order chromatin organization in the INK4/ARF locus in a reprogrammed cell<ref name="PMID22340434"/>. Additionally, the chromatin decompation in the INK4/ARF locus shown in the OIS cells coupled with induction of the INK4 genes and senescence-associated nuclear changes may be a barrier for reprogramming to iPS cells<ref name="PMID22340434"/><ref name="PMID19668188"/>.

'''References'''
<references/>

==Lab Attendance==
Lab 1 --[[User:Z3333038|Z3333038]] 11:49, 25 July 2012 (EST)

Lab 2 --[[User:Z3333038|Z3333038]] 10:05, 1 August 2012 (EST)

Lab 3 --[[User:Z3333038|Z3333038]] 10:01, 8 August 2012 (EST)

Lab 4 --[[User:Z3333038|Z3333038]] 10:00, 15 August 2012 (EST)

Lab 5 --[[User:Z3333038|Z3333038]] 09:59, 22 August 2012 (EST)

Lab 6 --[[User:Z3333038|Z3333038]] 10:10, 29 August 2012 (EST)

Lab 7 --[[User:Z3333038|Z3333038]] 10:09, 12 September 2012 (EST)

Lab 8 --[[User:Z3333038|Z3333038]] 10:00, 19 September 2012 (EST)

Lab 9 --[[User:Z3333038|Z3333038]] 10:03, 26 September 2012 (EST)

Lab 10 --[[User:Z3333038|Z3333038]] 10:04, 3 October 2012 (EST)

Lab 11 --[[User:Z3333038|Z3333038]] 10:18, 10 October 2012 (EST)

Lab 12 --[[User:Z3333038|Z3333038]] 09:39, 17 October 2012 (EST)

User:Z3333038

2012-10-16T22:35:04Z

Z3333038: /* Lab 11 Assessment */

User:Z3333038

2012-10-16T22:28:45Z

Z3333038: /* Lab 11 Assessment */

==Individual Assessments==

===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 History of In Vitro Fertilisation====
In vitro fertilisation (IVF) refers to the process of artificial fertilisation conducted ex vivo. The IVF technique was first described for non-human use. The earliest known research conducted was by Walter Heape from Cambridge University in the 1890s who reported the first known case of embryo transplantation in rabbits. In 1959, Dr. Min Chueh Chang published his work in Nature describing the first successful mammalian live birth (rabbits) after IVF therapy.

Eventually, the use of IVF for humans became a possibility and then a reality: in 1978, the first successful birth from IVF occurred in England. The success of this IVF birth is credited to Patrick Steptoe and Robert Edwards. In 2010, Edwards was awarded the [http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/ Nobel Prize in Medicine] for the development of human IVF therapy. Because of IVF, many couples have been given a chance to conceive. However, the [http://www.ivf-worldwide.com/ivf-history.html/ history of IVF] is still in the making with constant improvements in the technology being developed and applied.

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

====Research in Fertilisation====

In order for fusion between mammalian gametes to occur, a spermatozoon must first pass through the external layers surrounding the oocyte: the cumulus oophorus and the zona pellucida (ZP). It is believe that the acromosome reaction (AR) of the spermatozoa starts upon contact with the zona pellucida. Consequently, the cumulus cell layer is typically removed in studies of mouse sperm-oocyte interactions in order to facilitate fertilisation. The recent experiments of Jin et al. <ref name="PMID21383182"><pubmed>21383182</pubmed></ref> sought to answer the question: "Where does the fertilising mouse spermatozoon begin the AR - in the cumulus [of the oocyte] or the zona pellucida?" Jin et al. <ref name="PMID21383182"/> utilised fluorescence microscopy and transgenic mouse spermatozoa to conduct their investigation. Additionally, Jin et al. <ref name="PMID21383182"/> used cumulus-free oocytes and cumulus-enclosed oocytes to study the role of the cumulus cells in fertilisation.

From the experiment, Jin et al. <ref name="PMID21383182"/> found that most fertilising spermatozoa begin the AR before their first contact with the ZP. The significance of this finding was that the spermatozoa with intact acromosomes at the ZP seldom had the ability to penetrate through <ref name="PMID21383182"/>. In contrast, spermatozoa which had already began the AR could easily penetrate the ZP. In regards to the role of the cumulus cells, it was found that cumulus-enclosed oocytes had a higher incidence of fertilisation compared to cumulus-free oocytes <ref name="PMID21383182"/>. Moreover, cumulus-free oocytes had an increased incidence of in vitro fertilisation when incubated with other cumulus-enclosed cells; this finding suggests that cumulus cells harbour an important role in fertilisation <ref name="PMID21383182"/>. However, it is notable that when cumulus-free oocytes were incubated in a cumulus-conditioned medium, no increase in fertilisation rate was noted<ref name="PMID21383182"/>. Overall, two conclusions were made: firstly, that the AR is required by the spermatozoa prior to meeting the ZP for effective fertilisation<ref name="PMID21383182"/>. Secondly, the cumulus oophorus confers benefit in increasing the chance of fertilisation<ref name="PMID21383182"/>.

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 16:58, 11 September 2012 (EST) Question 1 is answered well and linked to appropriate resources. Question 2 is also quite a complete answer to what I requested. The formatting of your description could have been better organised, while it is correct to cite the paper when referring to the findings, this is a little overboard with 9 times within 2 paragraphs. If you had organised the information differently this could have been reduced to 1-2 citations within the text. Alternatively the findings could have been provided as a bullet or numbered list. '''10/10'''

===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.''
====Patterns of ZPC Deposition in Porcine Oocyte-Cumulus Complexes====
[[File:Patterns_of_ZPC_Deposition_in_Porcine_Oocytes.jpg‎]]

Immunofluorescence Detection for ZPC and Ubiquitin in a Porcine Oocyte <ref name="PMID21383844"><pubmed>21383844</pubmed></ref>

'''References'''
<references/>

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

Trophinin is a membrane protein expressed in chorionic villi trophoblasts and in the maternal endometrium. In the early stages of pregnancy, trophinin is strongly expressed along with tastin and bystin, which form a complex; this complex mediates apical cell adhesion between the trophoblasts and the endometrial epithelial cells<ref name="PMID14633596"><pubmed>14633596</pubmed></ref>. The time frame in which trophinin is expressed on the apical aspect of the endometrial cells coincides with the "implantation window"<ref name="PMID14633596"/>; the period in which successful implantation is possible. Trophonin-trophonin adhesion during implantation occurs via signal transduction with bystin and tastin<ref name="PMID22201876"><pubmed>22201876</pubmed></ref>. As a consequence of trophinin-trophinin adhesion, trophectoderm cells become activated for implantation<ref name="PMID22201876"/>. Moreover, there have been reports that endometrial epithelial cells undergo apoptosis upon blastocyst adhesion; human trophoectoderm cells express the Fas ligand which interacts with Fas expressed on the endometrium<ref name="PMID22201876"/>. However, other studies have shown that trophinin-mediated cell adhesion can induce endometrial cell apoptosis through mechanisms other than the Fas/FasL cascade<ref name="PMID22201876"/>.

In regards to ectopic pregnancies located within the fallopian tube, research has shown that trophinin is strongly expressed by both the embryonic trophoblasts and maternal fallopian tube epithelium, induced by human chorionic gonadotrophin (hCG)<ref name="PMID14633596"/>. These findings highlight the function of trophonin in facilitating implantation in conjunction with its role in the pathogenesis of ectopic pregnancies.

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 17:04, 11 September 2012 (EST) Question 1 image has been correctly uploaded and contains all the requested information in the summary box. Question 2 is a good description of this recent paper on trophinin and Implantation. '''10/10'''

===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.''
====Gestational Age versus Post-Fertilisation Age====

Gestation is the period of time between conception and birth (Kaneshiro, 2011; Vishton, 2011). Gestational age is the developmental age of the conceptus based on the presumed first day of the last normal menstrual period to the current date, measured in weeks (Kaneshiro, 2011; Vishton, 2011). In contrast, post-fertilisation age refers to the age of the conceptus expressed in elapsed time since fertilisation (Vishton, 2011). Gestational age is approximately two weeks greater than post-fertilization age (Kaneshiro, 2011; Vishton, 2011). Gestational age is used in human development because its start date can be determined by asking the mother when was the presumed first day of the last normal menstrual period (Kaneshiro, 2011; Vishton, 2011). In contrast, the moment of fertilization must be inferred (Vishton, 2011).

'''References'''

Kaneshiro, N. K. (2011). ''Gestational age''. Retrieved from http://www.umm.edu/ency/article/002367.htm

Vishton, P. M. (2011). ''Embryo Foetus Development Stages''. Retrieved from http://www.livestrong.com/article/92683-embryo-fetus-development-stages/

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

====Tissues Derived From Somites====

'''1. Bone (Sclerotome)'''

Bone tissue consists of cells separated by an extracellular matrix with organic and inorganic components (Marieb, Wilhem & Mallatt, 2010). The organic components of bone consists of cells, collagen fibres and ground substance. The cells include osteoprogenitor cells which give rise to osteoblasts: the producers of new bone matrix (osteoid). Mature osteoblasts, called osteocytes, are trapped in lacunae where they maintain the mature bone; osteocytes may revert to osteoblasts in the incidence of a fracture. Osteoclasts are multinucleated cells with ruffled plasma membrane borders and are involved in bone resorption. Bone resorption is important for bone remodelling to improve tensile strength as well as remodel the newly deposited woven bone into mature bone after a fracture. There are two types of mature (lamellar) bone: compact bone and spongy bone (Marieb et al., 2010). The compact bone occurs towards the periphery and is arranged in Haversian systems: lamellae concentrically arranged around a central Haversian canal containing blood vessels, nerves and osteocytes (Marieb et al., 2010). The different Haversian systems communicate with each other, the periosteum and endosteum through the Volkmann's canals. In contrast, spongy bone in the mature adult appears towards the centre of the diaphysis and metaphysis and is arranged in bony shelves (trabeculae) (Marieb et al., 2010). The gross porous arrangement of spongy bone is important for housing the bone marrow (Marieb et al., 2010)

'''2. The Skin (Dermotome)'''

a. ''Dermis'': The dermis is made up of two main regions: (1) the superficial papillary layer and (2) the deeper reticular layer (Marieb et al., 2010). The superficial papillary layer makes up 20% of the dermis and is areolar connective tissue consisting of collagen and elastic fibres; it includes the dermal papillae which extend into the overlying epidermis to strengthen the dermal-epidermal junction and increase surface area for nutrient, gas and waste exchange with the avascular epidermis (Marieb et al., 2010). The reticular layer is composed of dense irregular connective tissue with thick bundles of collagen and elastic fibres arranged in different planes (Marieb et al., 2010). Other cells interspersed among the connective tissue of the dermis include fibroblasts, macrophages, mast cells and other white blood cells including lymphocytes(Marieb et al., 2010). The dermis is highly vascular and supplied with nerve fibres (Marieb et al., 2010). There are two vascular plexuses; the deep dermal plexus and the subpapillary plexus (Marieb et al., 2010). These vessels serve not only for nutrient supply to the dermis and epidermis, but for temperature regulation as well (Marieb et al., 2010).

b. ''Hypodermis'': The subcutaneous layer, or fatty hypodermis, consists of areolar and adipose connective tissue(Marieb et al., 2010). The cellular components include adipocytes as well as white blood cells (Marieb et al., 2010). The hypodermis serves to store fat and anchor the skin to underlying structure in a manner that the skin can slide over structures(Marieb et al., 2010). Additionally, the adipose in the hypodermis serves an insulator.

'''3. Skeletal Muscle (Myotome)'''
Skeletal muscle fibres come together to form a larger skeletal muscle surrounded by different levels of connective tissue "coats": the epimysium surrounds the whole skeletal muscle, the perimysium covers each fascicle and the loose CT endomysium separates each skeletal muscle fibre (Marieb et al., 2010). The skeletal muscle fibres are long cylindrical cells with a diameter between 10-100um (Marieb et al., 2010) . These muscle fbres are formed by the fusion of embryonic cells and hence contain many nuclei which are located at the periphery of each fibre beneath the sarcolemma, the skeletal muscle cell membrane (Marieb et al., 2010). These muscle fibres appear striated because of the internal organelles of the muscle fibres: myofibrils, the contractile organelles of muscle tissue (Marieb et al., 2010).

'''References'''

Marieb, E. N., Wilhelm, P. B., Mallatt, J. (2010). ''Human Anatomy'' (6th ed.). San Francisco, CA: Pearson Education, Inc.

--[[User:Z8600021|Mark Hill]] 17:10, 11 September 2012 (EST) Question 1 Clearly identified and cited the difference between "gestational age" and "post-fertilisation age". Question 2 you have also identified histological descriptions at least 3 different types of tissues formed from somites. For both questions you could have formatted the references and the reference list by using the <nowiki><ref></ref></nowiki> tags and simply inserted any text that you wanted in your list between the tags. '''10/10'''

===Lab 4 Assessment===

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

*'''Amniocentesis''' <ref>Moore, K. L., Persaud, T. V. N. & Torchia, M. G. (2013). ''The Developing Human'' (9th ed.). Philadelphia, PA: Elsevier Saunders. </ref>: Amniocentesis refers to sampling of the amniotic fluid by inserting a needle through the mother's anterior abdominal and uterine walls into the amniotic cavity by piercing the chorion and amnion. This technique is performed at 15 and 18 weeks gestation. Amniocentesis is often used to detect genetic disorders as it allows for chromosome analysis. One abnormality which can be detected is trisomy 21 (Down's Syndrome)[1]. Additionally, amniocentesis can be utilised for alpha-fetoprotein assays to detect neural tube defects like spina bifida [1].

*'''Chorionic Villus Sampling''' [1]: Biopsies of trophoblastic tissue are obtained by inserting a needle through the mother's abdominal wall and uterine walls to the uterine cavity. Sampling can also be performed through the cervix with a polyethylene catheter, guided by real-time ultrasonography. CVS can be performed sooner than amniocentesis at 10 and 12 weeks of gestation. However, the rate of miscarriage from CVS is higher than amniocentesis. Like amniocentesis, CVS can be used to detect chromosomal abnormalities like trisomy 21 as well as trisomy 18. Additionally, Tay-Sachs disease can be detected with CVS [1].

====The Therapeutic Use of Cord Stem Cells====
''2. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.''

Fu et al. (2006) sought to isolate human umbilical cord mesenchymal stem cells (HUCMSCs) and transform them into dopaminergic neurons in vitro <ref name="PMID16099997"><pubmed>16099997</pubmed></ref>. The experiment was carried out in the interest of finding a potential cure for Parkinson's disease from HUCMSCs [2]. The procedure involved isolating human mesenchymal stem cells from Wharton's jelly of the umbilical cord and culturing the HUCMSCs in a neuronal conditioned medium (NCM) [2]. The differentiation of the HUCMSCs into dopaminergic neurons was induced through stepwise culturing with the NCM, sonic hedgehog and FGF-8 [2]. The successfully transformed HUCMSCs into dopaminergic neurons were selected by positive immunohistochemistry staining for tyrosine hydroxylase (TH), the rate-limiting catecholaminergic synthesizing enzyme, and dopamine secretion [2]. These neurons were then transplanted into the striatum of rats with induced Parkinson's disease by unilateral striatal lesioning with neurotoxin (6-hydroxydopamine hydrogen chloride)[2]. The effects of stem cell transplantation were examined in the Parkinsonian animals by quantification of rotations in the mice in response to amphetamine at 0, 1, 2, 3 and 4 months [2].

Despite a success rate of 12.7% of transformed HUCMSCs, the study found that the original number of HUCMSCs doubled after 3 days of culture [2]. Additionally, the transformed HUCMSCs were still viable in the rats 4 months post-transplantation without the need for immunosuppression [2]. These findings highlight HUCMSCs as a potentially safe source of organs due to their viability post-surgery and the lack of a negative host response to the newly transplanted tissues. Additionally, positive TH staining showed migration of the transformed HUCMSCs rostrally and caudally from the location of implantation [2]. Hence, the transformed HUMSCs were able to integrate properly into the patient (Parkinsonian mouse), putting forth their suitability as a tissue source for transplantation.

The clinical effects of the HUCMSCs on the Parkinsonian mice were assessed by comparing test subjects to two control groups. The first control group consisted of normal, non-Parkinsonian mice with a low score of rotation in response to amphetamine. The second control group contained Parkinsonian mice which received no treatment and had a high rotation score [2]. It was found that the second control group showed no improvement in rotation score and deteriorated further over time. Similarly, mice treated with non-transformed HUCMSCs did not have observable improvements and had a similar deteriorating rotation score to the untreated Parkinsonian animals [2]. This finding highlights that untransformed HUCMSCs confer no clinical benefit in the setting of simulated Parkinson's disease [2]. The Parkinsonian mice treated with transformed HUCMSCs at first had no observable improvement but over time showed significantly improved rotational scores relative to the Parkinsonian control group [2]. However, the transformed HUCMSCs group did not show improvement to the extent of returning to a normal level (non-Parkinsonian rat). These findings suggest that HUCMSCs could be a potential stem cell source for transplantation, however, the procedures for HUMSCs transformation and transplantation must first be reviewed [2]. Fu et al. (2006) suggested that, the number of dopaminergic neurons of implanted cells may have been relatively inadequate to alleviate the Parkinsonism symptoms in the affected rats. Additionally, the transplanted cells may take time to integrate into the host brain: only two rats in the transformed HUCMSCs group survived for at least 8 months, with amphetamine-induced rotation behavior remaining similar to that 4 months after transplantation. Hence, in order to properly assess HUCMSCs to treat Parkinson's disease, the long-term effects of transplantation must be studied [2].

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 17:18, 11 September 2012 (EST) Question 1 well answered in terms of technique and specific abnormalities. Question 2 human umbilical cord mesenchymal stem cells in Wharton's jelly have been used in several studies as potential sources of therapeutic cells. Perhaps a more recent paper next time. '''10/10'''

===Lab 7 Assessment===

====Muscle Satellite Cells====

''1. (a) Provide a one sentence definition of a muscle satellite cell''

Satellite cells are quiescent cells located beneath the basal lamina of each myofibre and function as myogenic precursors (stem cells) for postnatal muscle growth and repair <ref name="PMID16051152"><pubmed>16051152</pubmed></ref>.

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

Muscle satellite cells are at rest (G0) when skeletal muscle is not active<ref name="PMID22649641"><pubmed>22649641</pubmed></ref>. Activation can occur in the settings of physical activity and mechanical trauma <ref name="PMID12892408"/>. When satellite cells are activated, they proliferate and are converted to myoblasts which further differentiate and fuse with existing muscle fibres or form new fibres <ref name="PMID12892408"><pubmed>12892408</pubmed></ref>. The myonuclei accumulated in the tissue are of key importance for myogenesis: they aid in increasing protein synthesis and enable muscle growth (hypertrophy and hyperplasia) and regeneration<ref name="PMID16051152"/>. Without satellite cells, mature muscle fibres are unable to undergo regeneration <ref name="PMID16051152"/>. There is much speculation as to the exact mechanisms and factors which activate muscle satellite cells. It is proposed that strenuous exercise, mechanical muscle injury or myodegenerative disease result in the inflammatory response which recruits neutrophils and macrophages to the area of damage; the inflammatory mediators released in conjunction with growth factors secreted by the myofibres promote myosatellite activation <ref name="PMID12892408"/>. One proposed "triggering agent" is the production of sphingosine-1-phosphate from the inner part of the plasma membrane leading to satellite cell entry into the cell cycle <ref name="PMID17996437"><pubmed>17996437</pubmed></ref>. Additionally, mechanical stretch to the muscle fibre has been shown to trigger intracellular signals, such as nitric oxide synthesis which results in hepatocyte growth factor (HGF) release <ref name="PMID17996437"/>. Nitric oxide also induces follistatin, a fusigenic secreted molecule, which is an antagonist to myostatin. Myostatin is expressed by quiescent satellite cells and exerts a negative effect on satellite cell activation <ref name="PMID17996437"/>. IGF-IEa and MGF have also been implicated in satellite cell activation: Hill et al. (2003) demonstrated that these mediators are produced by active muscle in rodents and appear to be positive regulators of muscle hypertrophy<ref name="PMID12892408"><pubmed>12892408</pubmed></ref>. However, whilst MGF is acutely induced and is said to precede satellite cell activation, IGF-IEa has a delayed effect involved in the later phase of regeneration<ref name="PMID12892408"/>. Interestingly, in dystrophic muscles MGF is not produced, suggesting the importance of effective muscle repair to avoid the pathogenesis of muscular dystrophy syndromes <ref name="PMID12892408"/>.

Once activated, the satellite cells migrate out of the basal lamina and enter the cell cycle with coexpression of Pax7 and MyoD <ref name="PMID17996437"/>. This process occurs in conjunction with the Notch signaling pathway<ref name="PMID22493066"><pubmed>22493066</pubmed></ref>. The skeletal myoblasts that are produced divide, express myogenin and downregulate Pax7 then fuse to form myofibres<ref name="PMID17996437"/>.

====The Effects of Motor Nerve Damage on Skeletal Muscle====

''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?''

Chronic spinal cord injury (SCI) affects muscles below the level of the lesion. In terms of fibre type, one review <ref name="PMID19705475"><pubmed>19705475</pubmed></ref>describes the progressive change in fibre type toward faster phenotypes. The fibre phenotype is classified according to its myosin heavy chain (MHC) molecule which is an actin-based motor protein associated with muscle fibre contraction<ref name="PMID19705475"/>. These three MHC isoforms are MHC I, MHC IIa, and MHC IIx <ref name="PMID19705475"/>. In SCI there is a reduction of type I fibres (slow) and upregulation of type IIA and IIX fibres (fast)<ref name="PMID19705475"/>. The metabolism of the fast fibres is characterised by a predominantly anaerobic metabolism with fewer mitochondria, unlike type I fibres which undergo aerobic metabolism <ref name="PMID19705475"/>. This is in part due to a reduction in absolute activities of the muscle metabolic enzymes in SCI, favouring the fast glycolytic/oxidative type which fatigue more easily <ref name="PMID19705475"/>.

In terms of fibre size, a study by Castro et al. (1998) <ref name="PMID9887150"><pubmed>9887150</pubmed></ref> found that all fibre types underwent significant atrophy and decreased in size from the 6th to 24th week after injury<ref name="PMID9887150"/>. Moreover, average fibre cross-sectional area decreased by 22% by the 6th week post-injury <ref name="PMID9887150"/>. The changes were accompanied by either complete paralysis or loss of force with increased susceptibility to fatigue depending on the extent of injury <ref name="PMID9887150"/>. Note that whilst type II fibre atrophy is seen during the first months after complete SCI, type I fibres undergo atrophy in the later stages <ref name="PMID19705475"><pubmed>19705475</pubmed></ref>.

Interestingly, the level of the motor neuron lesion can affect the outcome of the muscle atrophy: a study by Stilwill and Sagha <ref name="PMID66912"><pubmed>66912</pubmed></ref>found that lower motor neuron lesions led to muscle fibre grouped atrophy and fibre-type grouping, whereas upper motor neuron lesions led to preferential atrophy of type II fibers with fibre-type grouping.

'''References'''
<references/>

===Lab 8 Assessment===
1. Each student should now look at each of the other Group projects in the class.

2. Next prepare a critical assessment (should include both positive and negative issues) of each project using the project assessment criteria.

3. This assessment should be pasted without signature on the top of the specific project's discussion page. (minimum length 3-5 paragraphs/project)

4. This critical assessment should also be pasted on your own student page. Each student should therefore have 5 separate reports pasted on their own page for this assessment item. Length, quality and accuracy of your reports will be part of the overall mark for this assessment (there will be a greater loading on this than simple question assessments).

====Vision====
In regards to the information presented (outcomes 1 and 9), as the project is still in progress it is understandable that some areas are incomplete. There is so far good, concise information on the structure of the development of the eye and the structures involved in vision. It would be useful to include information on the genetic factors involved in vision development as well as have a section explaining the processes involved with vision. Also, for the Current Research section (outcome 5), it would be better to explain the aims and findings of the research papers cited rather than just referencing the papers and images without describing their significance to research progress. In terms of peer teaching (outcome 4), the page contains a good balance between technical terms and simple language for understanding on the development of structures for vision; additionally, the inclusion Glossary helps to clarify any technical terms.

The most striking part of the layout (outcome 2) is the use of images to demonstrate the development of structures involved in vision. This is great because it makes the page interesting and provides a visual understanding on the development of the eye. However, at times the images could be better placed: for example, in the introduction the pictures appear stacked on top of one another. Additionally, the images in the introduction show similar structures, so perhaps select only one to better aid the flow and appearance of the page. Throughout the page, the images utilised could be provided with more description and linked to the text in order to improve flow and enhance written explanation. Perhaps some information, such as the timeline, could be sorted into a table to improve the layout.

In regards to outcome 3, some of the information provided (e.g. in the section on Development) is not referenced. Additionally, some of the references in the Reference list need to be formatted correctly with author, date, title of the page, publisher (if required) and any other necessary information. It would be useful to follow the style of the automatic default referencing.
Hope the feedback helps and all the best with your project!

====Somatosensory====
The introduction is good in that there is a description of the role of somatosensory functions as well as an overview of its development. To improve further, perhaps avoid trailing off in the final sentence and perhaps put something that concludes your introduction.

In regards to the information presented and layout (outcomes 1, 2, 4 and 9), the history of discoveries is very brief and requires more research. Additionally, it would be useful to set up a timeline to add interest. The section on the central somatosensory differentiation appeared very well researched with a very interesting picture to accompany the text – good work. The section on Touch would better be placed in a table and have accompanying images to avoid getting too ‘wordy’. Also, this section does not have any consistent referencing in the bulk of the content – please cite where you find your information. The section on pain is well researched and has a strong content, however, to enhance this section I would suggest using dot points to describe the different fibres and add a relevant image. Similarly, the hot/cold and pressure sections were great in terms of content but could use with some dot points and visual explanation to make the page more interesting. Just a note on pressure – avoid getting repetitive; the page had already defined the Ruffini’s endings/corpuscles etc in the section of Touch. Additionally, the 2 urls at the bottom of this section are distracting, make sure to incorporate these in your reference list of add them to an ‘External Links’ section. Your Current Research section requires some proof reading and additional articles to make it more comprehensive. However, you have referenced the image well and referred to it in the accompanying text.

In terms of referencing, I noticed some areas where the in-text references were not correctly formatted and were in the (Author, date) style. Perhaps have a look at the referencing tutorial on the Embryology ‘Students’ page to get an understanding of the codes required for citations. For peer teaching (outcome 4), make sure that you define all technical terms – your Glossary only has 2 definitions provided. Other than this, the content overall is interesting to read just make sure you are striking a balance between images and text. Hope it helps and all the best!

====Taste====

In regards to the information presented (outcomes 1 and 9), the timeline for the development is good and written with clarity. However, I noticed the section on structure only referred to the adult state rather than focusing on the embryonic origin of each structure (ectoderm, endoderm and mesoderm). I would suggest that you elaborate on the developmental stages introduced in the timeline in order to build on the information you have already provided. This is important in regards to outcome 6 so that you can relate your research to embryology – the development of taste should be your focus. The history timeline was great to read as it was very concise and clear.

The page shows a good level of peer teaching with clear language and a good balance between images and text (outcome 4) with technical terms explained in the glossary. An improvement could be to make a link between any technical language and the glossary to avoid scrolling up and down to the page. Your Current Research section (outcome 5) was very interesting to read and showed you went beyond the scope of basic research on taste – good work!

In terms of layout (outcome 2), whilst the images are interesting and relevant to the text, some are not appropriately referenced nor described; make sure to reference appropriately and at least write one or two sentences to make the images relevant to the reader. Additionally, the introduction should not be under another subheading (Gustatory system) as it creates some confusion; I would suggest making the introduction its own heading in order to make the page flow. Similarly, the history timeline would best be placed towards the beginning of the page, under the introduction.

I noticed some areas (such as the section on Structure) were not appropriately or consistently referenced. Make sure to include a citation anytime you introduce a researched idea or information to avoid being accused of plagiarism. I noticed the history timeline had good consistent referencing; however the numbers just need to be formatted so they come under the reference list. If you click on the Tutorial: References page linked from the student page, it tells you how to do this. Hope the feedback helps and all the best for your project!

====Abnormal Vision====
"The introduction is good in the manner that it provides some brief background information regarding the normal development of the eye and abnormalities. Additionally, I liked how the introduction described the aims of the page because it sets up a structure for the reader to follow. Just make sure to proof read this section: “The development of the eye is very sensitive and REQUIRES accurate...”

In regards to the information presented and layout (outcomes 1, 2, 4 and 9):

1. Normal Eye Development: This section appears very well researched. I like how you referred to the stages throughout development. However, this section could be enhanced by adding an image of the normal eye structure and development – this acts as a reference point for your page viewers, allowing for a clear visual comparison between the abnormalities and normal structure.

2. Abnormal Development: I like the overview provided at the beginning as it sets the scene for what points you will be covering in this section. Great job. All sections are quite good, just perhaps include more images to further enhance your page.

a. Abnormal lens development: I liked how you first described the function of the gene in development and then stated any abnormalities that arise when the gene is not expressed or mutated. I liked how you included an image for the crystalline genes; just make sure to refer to the image in text (e.g. see fig. 1. or see accompanying image).

b. Abnormal corneal development: Similar to the abnormal lens section, there is a good explanation provided for each gene involved. Just some improvements: make sure to reference all information; e.g. No reference provided for “The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of....”. The accompanying image has been referenced correctly and described, good work!

c. Abnormal retinal development: Once again, a great scope of research and information and suitable image. I liked how you described the impact of each mutation explicitly such as in Albinism “ganglion cells of retina decreased by 25%”. This really helps the reader to understand the extent of the abnormalities from certain gene mutations.

3. Ocular manifestations: the opening sentence is slightly vague. Could you please state which two separate sections that you are referring to? The section that follows could be better organised. It seems to jump from genetic issues to a research timeline then to future research on that disease to another example of a genetic mutation which produces abnormalities. I would suggest putting the research timeline shortly after the introduction and integrating research history not just on LCA but other abnormalities as well. However, the content for all these sections is well referenced and interesting to read. The balance between text and images between LCA and anopthalmia/micropthalmia sections is good and are both really interesting to read! I liked how you provided some epidemiological data and clinical manifestations in depth accompanied by suitable images. However, the environmental abnormalities section could use with more dot-point styles and images to enhance the presentation and aid in your descriptions.

In regards to peer teaching (outcome 5), this page was an absolute joy to read and all technical language was explained in the glossary. Just make sure to pay attention to those minor improvements. Good job!"

====Hearing====

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

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

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

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

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

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

===Lab 9 Assessment===

====Embryonic Blood Flow and Oxygen and the Developing Pancreas====

''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.''

A study by Shah et al.<ref name="PMID21050843"><pubmed>21050843</pubmed></ref> sought to investigate whether enhanced blood flow and oxygen in a developing mouse pancreas correlates with changes in differentiation during embryonic pancreatic development. This investigation was prompted because "there is a fundamental lack of understanding of how organs in early mammalian embryos are able to form despite receiving little or no blood flow" according to Shah et al.

The methods involved injecting fluorescein-conjugated tomato lectin (a vascular tracer) into the hearts of developing mouse embryos ''in utero'' at different stages of development, guided by ultrasound backscatter microscopy. The vascular tracer was left to circulate for 10 minutes and then the mice embryos were harvested for analysis of blood flow and oxygenation. One key finding discovered through immunohistochemistry was that the developing pancreas had dense vascularity, though numerous vessels early in gestation were non-perfused. Vessels that were not perfused with blood did not induce differentiation of adjacent pancreatic epithelium. In contrast, vessels perfused with blood were surrounded by glucagon-positive and insulin-positive cells; these are indications of pancreatic cell differentiation. However, ''in vitro'' it was found that the hypoxic embryonic pancreas shows proliferation but not differentiation. Interestingly, the endocrine areas tended to be areas with flow and higher oxygenation compared to the exocrine areas of the pancreas. Moreover, later embryonic stages when global pancreatic perfusion occurred correlated with a rapid increase in exocrine differentiation. Overall, Shah et al. concluded that vascular flow with oxygenated blood, as opposed to just vascular endothelium alone, may provide specific signals for pancreatic differentiation in the early embryo.

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

Through the interaction between the neural crest and the ectoderm, 10 teeth buds form in the the embryo on in the early embryo<ref>Universities of Fribourg, Lausanne and Bern. (2012). ''Development of the Teeth''. Retrieved from http://www.embryology.ch/anglais/sdigestive/gesicht05.html</ref>. Each tooth bud has an outer area of ectodermal orgign (the enamel organ) with an inner area of dental pulp made up of solidified mesenchyme of neuroectodermal origin. The neuroectodermal mesenchyme also forms the dental follicle from which the periodontium and cement of the tooth root arise.

* '''Ectoderm''' of the oral cavity produces:
** Ameloblasts which produce the teeth enamel in the direction of the tooth pulp.
* Surrounding '''mesoderm''' (mesenchyme) in conjunction with '''neural crest''' produces:
** Odontoblasts excrete predentin below the ameloblast layer; dentin then arises through calcium salt deposition in the predentin.
** Cementoblasts in the root of the tooth produce cement.

'''References'''
<references/>

===Lab 11 Assessment===

''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.''

The CCCTC-binding factor, CTCF, has been shown in the past to be involved in transcriptional control and chromatin interactions within the cell’s nucleus<ref name="PMID20020479"><pubmed>20020479</pubmed></ref>. A recent study by Hiroseu et al. <ref name="PMID22340434"><pubmed>22340434</pubmed></ref> sought to analyse the role of CTCF in induced pluripotent stem cells (iPS) by examining three cell lines: iPS cells induced from fibroblasts (201B7), human diploid fibroblasts (IMR90) and IMR90 cells undergoing oncongene-induced senescence (OIS) after Ras activation.

Hiroseu et al. noticed that CTCF mRNA was up-regulated in the iPS cells and down-regulated in the OIS cells in comparison to the IMR90 cells<ref name="PMID22340434"/>. Similarly, high levels of CTCF protein were expressed in the iPS cells whilst the OIS cells showed little CTCF protein expression <ref name="PMID22340434"/>. In order to clarify these results, Hiroseu et al. studied the interaction between CTCF and the and the INK4/ARF locus which encodes p15INK4b, p16INK4a and ARF: reprogramming regulators in the cell cycle which induce senescence<ref name="PMID19668188"><pubmed>19668188</pubmed></ref>. Using genome wide assay as well as CTCF binding profiles from data from past experiements, Hiroseu et al. where able to identify three CTCF enriched sites in the INK4/ARF locus: IC1, IC2 and IC3<ref name="PMID22340434"/>. These findings are of significance as they suggest a relationship between CTCF function and INK4/ARF transcription.

Chromatin precipitation showed that CTCF could bind to IC1, IC2 and IC3 in all three cell lines<ref name="PMID22340434"/>. The affinity of CTCF binding was found to be significantly high in the iPS cells compared to IMR90 cells<ref name="PMID22340434"/>. Additionally, chromosome conformation capture assay showed that in both the iPS cells and IMR90 cells, p15INK4b, p16INK4a and ARF were silenced<ref name="PMID22340434"/>. In contrast, the OIS cells showed weak CTCF binding with increased expression of p15INK4b and p16INK4a<ref name="PMID22340434"/>. Data analysis uncovered that the inverse relationships of expression are a result of the interaction between the CTCF enriched sites and the , p15INK4b, p16INK4a and ARF promoters<ref name="PMID22340434"/>. IC1 and IC2 strongly interacted with the p15INK4b and ARF promoters respectively<ref name="PMID22340434"/>. Moreovereover, the IC1/ p15INK4band IC2/ARF “binding site-promotor complexes”, the p16INK4a promoter and IC3 were found to be colocalised in the nucleus; Hiroseu et al. suggested that these gene interactions involve the formation of chromosome loops in the INK4/ARG locus<ref name="PMID22340434"/>. This hypothesis was supported by CTCF knockdown which was found to decrease the colocalisation of the genes, leading to a looser chromatin formation; this was coupled with increased expression of p15INK4b, p16INK4a <ref name="PMID22340434"/>. From these findings, Hiroeu et al. drew the conclusion that the CTCF complex is important for compact chromatin formation at the INK4/ARF locus<ref name="PMID22340434"/>.

In OIS cells, chromatin was found to undergo active decompaction which was related to its senescence as it allowed the expression of p15INK4b and p16INK4a<ref name="PMID22340434"/>. In contast, repressive compaction and intermediate compaction was demonstrated in the IMR90 and iPS cells respectively, explaining the silencing of the genes in the INK4/ARF locus<ref name="PMID22340434"/>. The implications of these findings for iPS research are two fold. Firstly, that CTCF is crucial for higher-order chromatin organization in the INK4/ARF locus in a reprogrammed cell<ref name="PMID22340434"/>. Additionally, the chromatin decompation in the INK4/ARF locus shown in the OIS cells coupled with induction of the INK4 genes and senescence-associated nuclear changes may be a barrier for reprogramming to iPS cells<ref name="PMID22340434"/><ref name="PMID19668188"/>.

'''References'''
<references/>

==Lab Attendance==
Lab 1 --[[User:Z3333038|Z3333038]] 11:49, 25 July 2012 (EST)

Lab 2 --[[User:Z3333038|Z3333038]] 10:05, 1 August 2012 (EST)

Lab 3 --[[User:Z3333038|Z3333038]] 10:01, 8 August 2012 (EST)

Lab 4 --[[User:Z3333038|Z3333038]] 10:00, 15 August 2012 (EST)

Lab 5 --[[User:Z3333038|Z3333038]] 09:59, 22 August 2012 (EST)

Lab 6 --[[User:Z3333038|Z3333038]] 10:10, 29 August 2012 (EST)

Lab 7 --[[User:Z3333038|Z3333038]] 10:09, 12 September 2012 (EST)

Lab 8 --[[User:Z3333038|Z3333038]] 10:00, 19 September 2012 (EST)

Lab 9 --[[User:Z3333038|Z3333038]] 10:03, 26 September 2012 (EST)

Lab 10 --[[User:Z3333038|Z3333038]] 10:04, 3 October 2012 (EST)

Lab 11 --[[User:Z3333038|Z3333038]] 10:18, 10 October 2012 (EST)

User:Z3333038

2012-10-16T22:25:04Z

Z3333038: /* Individual Assessments */

==Individual Assessments==

===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 History of In Vitro Fertilisation====
In vitro fertilisation (IVF) refers to the process of artificial fertilisation conducted ex vivo. The IVF technique was first described for non-human use. The earliest known research conducted was by Walter Heape from Cambridge University in the 1890s who reported the first known case of embryo transplantation in rabbits. In 1959, Dr. Min Chueh Chang published his work in Nature describing the first successful mammalian live birth (rabbits) after IVF therapy.

Eventually, the use of IVF for humans became a possibility and then a reality: in 1978, the first successful birth from IVF occurred in England. The success of this IVF birth is credited to Patrick Steptoe and Robert Edwards. In 2010, Edwards was awarded the [http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/ Nobel Prize in Medicine] for the development of human IVF therapy. Because of IVF, many couples have been given a chance to conceive. However, the [http://www.ivf-worldwide.com/ivf-history.html/ history of IVF] is still in the making with constant improvements in the technology being developed and applied.

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

====Research in Fertilisation====

In order for fusion between mammalian gametes to occur, a spermatozoon must first pass through the external layers surrounding the oocyte: the cumulus oophorus and the zona pellucida (ZP). It is believe that the acromosome reaction (AR) of the spermatozoa starts upon contact with the zona pellucida. Consequently, the cumulus cell layer is typically removed in studies of mouse sperm-oocyte interactions in order to facilitate fertilisation. The recent experiments of Jin et al. <ref name="PMID21383182"><pubmed>21383182</pubmed></ref> sought to answer the question: "Where does the fertilising mouse spermatozoon begin the AR - in the cumulus [of the oocyte] or the zona pellucida?" Jin et al. <ref name="PMID21383182"/> utilised fluorescence microscopy and transgenic mouse spermatozoa to conduct their investigation. Additionally, Jin et al. <ref name="PMID21383182"/> used cumulus-free oocytes and cumulus-enclosed oocytes to study the role of the cumulus cells in fertilisation.

From the experiment, Jin et al. <ref name="PMID21383182"/> found that most fertilising spermatozoa begin the AR before their first contact with the ZP. The significance of this finding was that the spermatozoa with intact acromosomes at the ZP seldom had the ability to penetrate through <ref name="PMID21383182"/>. In contrast, spermatozoa which had already began the AR could easily penetrate the ZP. In regards to the role of the cumulus cells, it was found that cumulus-enclosed oocytes had a higher incidence of fertilisation compared to cumulus-free oocytes <ref name="PMID21383182"/>. Moreover, cumulus-free oocytes had an increased incidence of in vitro fertilisation when incubated with other cumulus-enclosed cells; this finding suggests that cumulus cells harbour an important role in fertilisation <ref name="PMID21383182"/>. However, it is notable that when cumulus-free oocytes were incubated in a cumulus-conditioned medium, no increase in fertilisation rate was noted<ref name="PMID21383182"/>. Overall, two conclusions were made: firstly, that the AR is required by the spermatozoa prior to meeting the ZP for effective fertilisation<ref name="PMID21383182"/>. Secondly, the cumulus oophorus confers benefit in increasing the chance of fertilisation<ref name="PMID21383182"/>.

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 16:58, 11 September 2012 (EST) Question 1 is answered well and linked to appropriate resources. Question 2 is also quite a complete answer to what I requested. The formatting of your description could have been better organised, while it is correct to cite the paper when referring to the findings, this is a little overboard with 9 times within 2 paragraphs. If you had organised the information differently this could have been reduced to 1-2 citations within the text. Alternatively the findings could have been provided as a bullet or numbered list. '''10/10'''

===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.''
====Patterns of ZPC Deposition in Porcine Oocyte-Cumulus Complexes====
[[File:Patterns_of_ZPC_Deposition_in_Porcine_Oocytes.jpg‎]]

Immunofluorescence Detection for ZPC and Ubiquitin in a Porcine Oocyte <ref name="PMID21383844"><pubmed>21383844</pubmed></ref>

'''References'''
<references/>

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

Trophinin is a membrane protein expressed in chorionic villi trophoblasts and in the maternal endometrium. In the early stages of pregnancy, trophinin is strongly expressed along with tastin and bystin, which form a complex; this complex mediates apical cell adhesion between the trophoblasts and the endometrial epithelial cells<ref name="PMID14633596"><pubmed>14633596</pubmed></ref>. The time frame in which trophinin is expressed on the apical aspect of the endometrial cells coincides with the "implantation window"<ref name="PMID14633596"/>; the period in which successful implantation is possible. Trophonin-trophonin adhesion during implantation occurs via signal transduction with bystin and tastin<ref name="PMID22201876"><pubmed>22201876</pubmed></ref>. As a consequence of trophinin-trophinin adhesion, trophectoderm cells become activated for implantation<ref name="PMID22201876"/>. Moreover, there have been reports that endometrial epithelial cells undergo apoptosis upon blastocyst adhesion; human trophoectoderm cells express the Fas ligand which interacts with Fas expressed on the endometrium<ref name="PMID22201876"/>. However, other studies have shown that trophinin-mediated cell adhesion can induce endometrial cell apoptosis through mechanisms other than the Fas/FasL cascade<ref name="PMID22201876"/>.

In regards to ectopic pregnancies located within the fallopian tube, research has shown that trophinin is strongly expressed by both the embryonic trophoblasts and maternal fallopian tube epithelium, induced by human chorionic gonadotrophin (hCG)<ref name="PMID14633596"/>. These findings highlight the function of trophonin in facilitating implantation in conjunction with its role in the pathogenesis of ectopic pregnancies.

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 17:04, 11 September 2012 (EST) Question 1 image has been correctly uploaded and contains all the requested information in the summary box. Question 2 is a good description of this recent paper on trophinin and Implantation. '''10/10'''

===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.''
====Gestational Age versus Post-Fertilisation Age====

Gestation is the period of time between conception and birth (Kaneshiro, 2011; Vishton, 2011). Gestational age is the developmental age of the conceptus based on the presumed first day of the last normal menstrual period to the current date, measured in weeks (Kaneshiro, 2011; Vishton, 2011). In contrast, post-fertilisation age refers to the age of the conceptus expressed in elapsed time since fertilisation (Vishton, 2011). Gestational age is approximately two weeks greater than post-fertilization age (Kaneshiro, 2011; Vishton, 2011). Gestational age is used in human development because its start date can be determined by asking the mother when was the presumed first day of the last normal menstrual period (Kaneshiro, 2011; Vishton, 2011). In contrast, the moment of fertilization must be inferred (Vishton, 2011).

'''References'''

Kaneshiro, N. K. (2011). ''Gestational age''. Retrieved from http://www.umm.edu/ency/article/002367.htm

Vishton, P. M. (2011). ''Embryo Foetus Development Stages''. Retrieved from http://www.livestrong.com/article/92683-embryo-fetus-development-stages/

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

====Tissues Derived From Somites====

'''1. Bone (Sclerotome)'''

Bone tissue consists of cells separated by an extracellular matrix with organic and inorganic components (Marieb, Wilhem & Mallatt, 2010). The organic components of bone consists of cells, collagen fibres and ground substance. The cells include osteoprogenitor cells which give rise to osteoblasts: the producers of new bone matrix (osteoid). Mature osteoblasts, called osteocytes, are trapped in lacunae where they maintain the mature bone; osteocytes may revert to osteoblasts in the incidence of a fracture. Osteoclasts are multinucleated cells with ruffled plasma membrane borders and are involved in bone resorption. Bone resorption is important for bone remodelling to improve tensile strength as well as remodel the newly deposited woven bone into mature bone after a fracture. There are two types of mature (lamellar) bone: compact bone and spongy bone (Marieb et al., 2010). The compact bone occurs towards the periphery and is arranged in Haversian systems: lamellae concentrically arranged around a central Haversian canal containing blood vessels, nerves and osteocytes (Marieb et al., 2010). The different Haversian systems communicate with each other, the periosteum and endosteum through the Volkmann's canals. In contrast, spongy bone in the mature adult appears towards the centre of the diaphysis and metaphysis and is arranged in bony shelves (trabeculae) (Marieb et al., 2010). The gross porous arrangement of spongy bone is important for housing the bone marrow (Marieb et al., 2010)

'''2. The Skin (Dermotome)'''

a. ''Dermis'': The dermis is made up of two main regions: (1) the superficial papillary layer and (2) the deeper reticular layer (Marieb et al., 2010). The superficial papillary layer makes up 20% of the dermis and is areolar connective tissue consisting of collagen and elastic fibres; it includes the dermal papillae which extend into the overlying epidermis to strengthen the dermal-epidermal junction and increase surface area for nutrient, gas and waste exchange with the avascular epidermis (Marieb et al., 2010). The reticular layer is composed of dense irregular connective tissue with thick bundles of collagen and elastic fibres arranged in different planes (Marieb et al., 2010). Other cells interspersed among the connective tissue of the dermis include fibroblasts, macrophages, mast cells and other white blood cells including lymphocytes(Marieb et al., 2010). The dermis is highly vascular and supplied with nerve fibres (Marieb et al., 2010). There are two vascular plexuses; the deep dermal plexus and the subpapillary plexus (Marieb et al., 2010). These vessels serve not only for nutrient supply to the dermis and epidermis, but for temperature regulation as well (Marieb et al., 2010).

b. ''Hypodermis'': The subcutaneous layer, or fatty hypodermis, consists of areolar and adipose connective tissue(Marieb et al., 2010). The cellular components include adipocytes as well as white blood cells (Marieb et al., 2010). The hypodermis serves to store fat and anchor the skin to underlying structure in a manner that the skin can slide over structures(Marieb et al., 2010). Additionally, the adipose in the hypodermis serves an insulator.

'''3. Skeletal Muscle (Myotome)'''
Skeletal muscle fibres come together to form a larger skeletal muscle surrounded by different levels of connective tissue "coats": the epimysium surrounds the whole skeletal muscle, the perimysium covers each fascicle and the loose CT endomysium separates each skeletal muscle fibre (Marieb et al., 2010). The skeletal muscle fibres are long cylindrical cells with a diameter between 10-100um (Marieb et al., 2010) . These muscle fbres are formed by the fusion of embryonic cells and hence contain many nuclei which are located at the periphery of each fibre beneath the sarcolemma, the skeletal muscle cell membrane (Marieb et al., 2010). These muscle fibres appear striated because of the internal organelles of the muscle fibres: myofibrils, the contractile organelles of muscle tissue (Marieb et al., 2010).

'''References'''

Marieb, E. N., Wilhelm, P. B., Mallatt, J. (2010). ''Human Anatomy'' (6th ed.). San Francisco, CA: Pearson Education, Inc.

--[[User:Z8600021|Mark Hill]] 17:10, 11 September 2012 (EST) Question 1 Clearly identified and cited the difference between "gestational age" and "post-fertilisation age". Question 2 you have also identified histological descriptions at least 3 different types of tissues formed from somites. For both questions you could have formatted the references and the reference list by using the <nowiki><ref></ref></nowiki> tags and simply inserted any text that you wanted in your list between the tags. '''10/10'''

===Lab 4 Assessment===

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

*'''Amniocentesis''' <ref>Moore, K. L., Persaud, T. V. N. & Torchia, M. G. (2013). ''The Developing Human'' (9th ed.). Philadelphia, PA: Elsevier Saunders. </ref>: Amniocentesis refers to sampling of the amniotic fluid by inserting a needle through the mother's anterior abdominal and uterine walls into the amniotic cavity by piercing the chorion and amnion. This technique is performed at 15 and 18 weeks gestation. Amniocentesis is often used to detect genetic disorders as it allows for chromosome analysis. One abnormality which can be detected is trisomy 21 (Down's Syndrome)[1]. Additionally, amniocentesis can be utilised for alpha-fetoprotein assays to detect neural tube defects like spina bifida [1].

*'''Chorionic Villus Sampling''' [1]: Biopsies of trophoblastic tissue are obtained by inserting a needle through the mother's abdominal wall and uterine walls to the uterine cavity. Sampling can also be performed through the cervix with a polyethylene catheter, guided by real-time ultrasonography. CVS can be performed sooner than amniocentesis at 10 and 12 weeks of gestation. However, the rate of miscarriage from CVS is higher than amniocentesis. Like amniocentesis, CVS can be used to detect chromosomal abnormalities like trisomy 21 as well as trisomy 18. Additionally, Tay-Sachs disease can be detected with CVS [1].

====The Therapeutic Use of Cord Stem Cells====
''2. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.''

Fu et al. (2006) sought to isolate human umbilical cord mesenchymal stem cells (HUCMSCs) and transform them into dopaminergic neurons in vitro <ref name="PMID16099997"><pubmed>16099997</pubmed></ref>. The experiment was carried out in the interest of finding a potential cure for Parkinson's disease from HUCMSCs [2]. The procedure involved isolating human mesenchymal stem cells from Wharton's jelly of the umbilical cord and culturing the HUCMSCs in a neuronal conditioned medium (NCM) [2]. The differentiation of the HUCMSCs into dopaminergic neurons was induced through stepwise culturing with the NCM, sonic hedgehog and FGF-8 [2]. The successfully transformed HUCMSCs into dopaminergic neurons were selected by positive immunohistochemistry staining for tyrosine hydroxylase (TH), the rate-limiting catecholaminergic synthesizing enzyme, and dopamine secretion [2]. These neurons were then transplanted into the striatum of rats with induced Parkinson's disease by unilateral striatal lesioning with neurotoxin (6-hydroxydopamine hydrogen chloride)[2]. The effects of stem cell transplantation were examined in the Parkinsonian animals by quantification of rotations in the mice in response to amphetamine at 0, 1, 2, 3 and 4 months [2].

Despite a success rate of 12.7% of transformed HUCMSCs, the study found that the original number of HUCMSCs doubled after 3 days of culture [2]. Additionally, the transformed HUCMSCs were still viable in the rats 4 months post-transplantation without the need for immunosuppression [2]. These findings highlight HUCMSCs as a potentially safe source of organs due to their viability post-surgery and the lack of a negative host response to the newly transplanted tissues. Additionally, positive TH staining showed migration of the transformed HUCMSCs rostrally and caudally from the location of implantation [2]. Hence, the transformed HUMSCs were able to integrate properly into the patient (Parkinsonian mouse), putting forth their suitability as a tissue source for transplantation.

The clinical effects of the HUCMSCs on the Parkinsonian mice were assessed by comparing test subjects to two control groups. The first control group consisted of normal, non-Parkinsonian mice with a low score of rotation in response to amphetamine. The second control group contained Parkinsonian mice which received no treatment and had a high rotation score [2]. It was found that the second control group showed no improvement in rotation score and deteriorated further over time. Similarly, mice treated with non-transformed HUCMSCs did not have observable improvements and had a similar deteriorating rotation score to the untreated Parkinsonian animals [2]. This finding highlights that untransformed HUCMSCs confer no clinical benefit in the setting of simulated Parkinson's disease [2]. The Parkinsonian mice treated with transformed HUCMSCs at first had no observable improvement but over time showed significantly improved rotational scores relative to the Parkinsonian control group [2]. However, the transformed HUCMSCs group did not show improvement to the extent of returning to a normal level (non-Parkinsonian rat). These findings suggest that HUCMSCs could be a potential stem cell source for transplantation, however, the procedures for HUMSCs transformation and transplantation must first be reviewed [2]. Fu et al. (2006) suggested that, the number of dopaminergic neurons of implanted cells may have been relatively inadequate to alleviate the Parkinsonism symptoms in the affected rats. Additionally, the transplanted cells may take time to integrate into the host brain: only two rats in the transformed HUCMSCs group survived for at least 8 months, with amphetamine-induced rotation behavior remaining similar to that 4 months after transplantation. Hence, in order to properly assess HUCMSCs to treat Parkinson's disease, the long-term effects of transplantation must be studied [2].

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 17:18, 11 September 2012 (EST) Question 1 well answered in terms of technique and specific abnormalities. Question 2 human umbilical cord mesenchymal stem cells in Wharton's jelly have been used in several studies as potential sources of therapeutic cells. Perhaps a more recent paper next time. '''10/10'''

===Lab 7 Assessment===

====Muscle Satellite Cells====

''1. (a) Provide a one sentence definition of a muscle satellite cell''

Satellite cells are quiescent cells located beneath the basal lamina of each myofibre and function as myogenic precursors (stem cells) for postnatal muscle growth and repair <ref name="PMID16051152"><pubmed>16051152</pubmed></ref>.

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

Muscle satellite cells are at rest (G0) when skeletal muscle is not active<ref name="PMID22649641"><pubmed>22649641</pubmed></ref>. Activation can occur in the settings of physical activity and mechanical trauma <ref name="PMID12892408"/>. When satellite cells are activated, they proliferate and are converted to myoblasts which further differentiate and fuse with existing muscle fibres or form new fibres <ref name="PMID12892408"><pubmed>12892408</pubmed></ref>. The myonuclei accumulated in the tissue are of key importance for myogenesis: they aid in increasing protein synthesis and enable muscle growth (hypertrophy and hyperplasia) and regeneration<ref name="PMID16051152"/>. Without satellite cells, mature muscle fibres are unable to undergo regeneration <ref name="PMID16051152"/>. There is much speculation as to the exact mechanisms and factors which activate muscle satellite cells. It is proposed that strenuous exercise, mechanical muscle injury or myodegenerative disease result in the inflammatory response which recruits neutrophils and macrophages to the area of damage; the inflammatory mediators released in conjunction with growth factors secreted by the myofibres promote myosatellite activation <ref name="PMID12892408"/>. One proposed "triggering agent" is the production of sphingosine-1-phosphate from the inner part of the plasma membrane leading to satellite cell entry into the cell cycle <ref name="PMID17996437"><pubmed>17996437</pubmed></ref>. Additionally, mechanical stretch to the muscle fibre has been shown to trigger intracellular signals, such as nitric oxide synthesis which results in hepatocyte growth factor (HGF) release <ref name="PMID17996437"/>. Nitric oxide also induces follistatin, a fusigenic secreted molecule, which is an antagonist to myostatin. Myostatin is expressed by quiescent satellite cells and exerts a negative effect on satellite cell activation <ref name="PMID17996437"/>. IGF-IEa and MGF have also been implicated in satellite cell activation: Hill et al. (2003) demonstrated that these mediators are produced by active muscle in rodents and appear to be positive regulators of muscle hypertrophy<ref name="PMID12892408"><pubmed>12892408</pubmed></ref>. However, whilst MGF is acutely induced and is said to precede satellite cell activation, IGF-IEa has a delayed effect involved in the later phase of regeneration<ref name="PMID12892408"/>. Interestingly, in dystrophic muscles MGF is not produced, suggesting the importance of effective muscle repair to avoid the pathogenesis of muscular dystrophy syndromes <ref name="PMID12892408"/>.

Once activated, the satellite cells migrate out of the basal lamina and enter the cell cycle with coexpression of Pax7 and MyoD <ref name="PMID17996437"/>. This process occurs in conjunction with the Notch signaling pathway<ref name="PMID22493066"><pubmed>22493066</pubmed></ref>. The skeletal myoblasts that are produced divide, express myogenin and downregulate Pax7 then fuse to form myofibres<ref name="PMID17996437"/>.

====The Effects of Motor Nerve Damage on Skeletal Muscle====

''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?''

Chronic spinal cord injury (SCI) affects muscles below the level of the lesion. In terms of fibre type, one review <ref name="PMID19705475"><pubmed>19705475</pubmed></ref>describes the progressive change in fibre type toward faster phenotypes. The fibre phenotype is classified according to its myosin heavy chain (MHC) molecule which is an actin-based motor protein associated with muscle fibre contraction<ref name="PMID19705475"/>. These three MHC isoforms are MHC I, MHC IIa, and MHC IIx <ref name="PMID19705475"/>. In SCI there is a reduction of type I fibres (slow) and upregulation of type IIA and IIX fibres (fast)<ref name="PMID19705475"/>. The metabolism of the fast fibres is characterised by a predominantly anaerobic metabolism with fewer mitochondria, unlike type I fibres which undergo aerobic metabolism <ref name="PMID19705475"/>. This is in part due to a reduction in absolute activities of the muscle metabolic enzymes in SCI, favouring the fast glycolytic/oxidative type which fatigue more easily <ref name="PMID19705475"/>.

In terms of fibre size, a study by Castro et al. (1998) <ref name="PMID9887150"><pubmed>9887150</pubmed></ref> found that all fibre types underwent significant atrophy and decreased in size from the 6th to 24th week after injury<ref name="PMID9887150"/>. Moreover, average fibre cross-sectional area decreased by 22% by the 6th week post-injury <ref name="PMID9887150"/>. The changes were accompanied by either complete paralysis or loss of force with increased susceptibility to fatigue depending on the extent of injury <ref name="PMID9887150"/>. Note that whilst type II fibre atrophy is seen during the first months after complete SCI, type I fibres undergo atrophy in the later stages <ref name="PMID19705475"><pubmed>19705475</pubmed></ref>.

Interestingly, the level of the motor neuron lesion can affect the outcome of the muscle atrophy: a study by Stilwill and Sagha <ref name="PMID66912"><pubmed>66912</pubmed></ref>found that lower motor neuron lesions led to muscle fibre grouped atrophy and fibre-type grouping, whereas upper motor neuron lesions led to preferential atrophy of type II fibers with fibre-type grouping.

'''References'''
<references/>

===Lab 8 Assessment===
1. Each student should now look at each of the other Group projects in the class.

2. Next prepare a critical assessment (should include both positive and negative issues) of each project using the project assessment criteria.

3. This assessment should be pasted without signature on the top of the specific project's discussion page. (minimum length 3-5 paragraphs/project)

4. This critical assessment should also be pasted on your own student page. Each student should therefore have 5 separate reports pasted on their own page for this assessment item. Length, quality and accuracy of your reports will be part of the overall mark for this assessment (there will be a greater loading on this than simple question assessments).

====Vision====
In regards to the information presented (outcomes 1 and 9), as the project is still in progress it is understandable that some areas are incomplete. There is so far good, concise information on the structure of the development of the eye and the structures involved in vision. It would be useful to include information on the genetic factors involved in vision development as well as have a section explaining the processes involved with vision. Also, for the Current Research section (outcome 5), it would be better to explain the aims and findings of the research papers cited rather than just referencing the papers and images without describing their significance to research progress. In terms of peer teaching (outcome 4), the page contains a good balance between technical terms and simple language for understanding on the development of structures for vision; additionally, the inclusion Glossary helps to clarify any technical terms.

The most striking part of the layout (outcome 2) is the use of images to demonstrate the development of structures involved in vision. This is great because it makes the page interesting and provides a visual understanding on the development of the eye. However, at times the images could be better placed: for example, in the introduction the pictures appear stacked on top of one another. Additionally, the images in the introduction show similar structures, so perhaps select only one to better aid the flow and appearance of the page. Throughout the page, the images utilised could be provided with more description and linked to the text in order to improve flow and enhance written explanation. Perhaps some information, such as the timeline, could be sorted into a table to improve the layout.

In regards to outcome 3, some of the information provided (e.g. in the section on Development) is not referenced. Additionally, some of the references in the Reference list need to be formatted correctly with author, date, title of the page, publisher (if required) and any other necessary information. It would be useful to follow the style of the automatic default referencing.
Hope the feedback helps and all the best with your project!

====Somatosensory====
The introduction is good in that there is a description of the role of somatosensory functions as well as an overview of its development. To improve further, perhaps avoid trailing off in the final sentence and perhaps put something that concludes your introduction.

In regards to the information presented and layout (outcomes 1, 2, 4 and 9), the history of discoveries is very brief and requires more research. Additionally, it would be useful to set up a timeline to add interest. The section on the central somatosensory differentiation appeared very well researched with a very interesting picture to accompany the text – good work. The section on Touch would better be placed in a table and have accompanying images to avoid getting too ‘wordy’. Also, this section does not have any consistent referencing in the bulk of the content – please cite where you find your information. The section on pain is well researched and has a strong content, however, to enhance this section I would suggest using dot points to describe the different fibres and add a relevant image. Similarly, the hot/cold and pressure sections were great in terms of content but could use with some dot points and visual explanation to make the page more interesting. Just a note on pressure – avoid getting repetitive; the page had already defined the Ruffini’s endings/corpuscles etc in the section of Touch. Additionally, the 2 urls at the bottom of this section are distracting, make sure to incorporate these in your reference list of add them to an ‘External Links’ section. Your Current Research section requires some proof reading and additional articles to make it more comprehensive. However, you have referenced the image well and referred to it in the accompanying text.

In terms of referencing, I noticed some areas where the in-text references were not correctly formatted and were in the (Author, date) style. Perhaps have a look at the referencing tutorial on the Embryology ‘Students’ page to get an understanding of the codes required for citations. For peer teaching (outcome 4), make sure that you define all technical terms – your Glossary only has 2 definitions provided. Other than this, the content overall is interesting to read just make sure you are striking a balance between images and text. Hope it helps and all the best!

====Taste====

In regards to the information presented (outcomes 1 and 9), the timeline for the development is good and written with clarity. However, I noticed the section on structure only referred to the adult state rather than focusing on the embryonic origin of each structure (ectoderm, endoderm and mesoderm). I would suggest that you elaborate on the developmental stages introduced in the timeline in order to build on the information you have already provided. This is important in regards to outcome 6 so that you can relate your research to embryology – the development of taste should be your focus. The history timeline was great to read as it was very concise and clear.

The page shows a good level of peer teaching with clear language and a good balance between images and text (outcome 4) with technical terms explained in the glossary. An improvement could be to make a link between any technical language and the glossary to avoid scrolling up and down to the page. Your Current Research section (outcome 5) was very interesting to read and showed you went beyond the scope of basic research on taste – good work!

In terms of layout (outcome 2), whilst the images are interesting and relevant to the text, some are not appropriately referenced nor described; make sure to reference appropriately and at least write one or two sentences to make the images relevant to the reader. Additionally, the introduction should not be under another subheading (Gustatory system) as it creates some confusion; I would suggest making the introduction its own heading in order to make the page flow. Similarly, the history timeline would best be placed towards the beginning of the page, under the introduction.

I noticed some areas (such as the section on Structure) were not appropriately or consistently referenced. Make sure to include a citation anytime you introduce a researched idea or information to avoid being accused of plagiarism. I noticed the history timeline had good consistent referencing; however the numbers just need to be formatted so they come under the reference list. If you click on the Tutorial: References page linked from the student page, it tells you how to do this. Hope the feedback helps and all the best for your project!

====Abnormal Vision====
"The introduction is good in the manner that it provides some brief background information regarding the normal development of the eye and abnormalities. Additionally, I liked how the introduction described the aims of the page because it sets up a structure for the reader to follow. Just make sure to proof read this section: “The development of the eye is very sensitive and REQUIRES accurate...”

In regards to the information presented and layout (outcomes 1, 2, 4 and 9):

1. Normal Eye Development: This section appears very well researched. I like how you referred to the stages throughout development. However, this section could be enhanced by adding an image of the normal eye structure and development – this acts as a reference point for your page viewers, allowing for a clear visual comparison between the abnormalities and normal structure.

2. Abnormal Development: I like the overview provided at the beginning as it sets the scene for what points you will be covering in this section. Great job. All sections are quite good, just perhaps include more images to further enhance your page.

a. Abnormal lens development: I liked how you first described the function of the gene in development and then stated any abnormalities that arise when the gene is not expressed or mutated. I liked how you included an image for the crystalline genes; just make sure to refer to the image in text (e.g. see fig. 1. or see accompanying image).

b. Abnormal corneal development: Similar to the abnormal lens section, there is a good explanation provided for each gene involved. Just some improvements: make sure to reference all information; e.g. No reference provided for “The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of....”. The accompanying image has been referenced correctly and described, good work!

c. Abnormal retinal development: Once again, a great scope of research and information and suitable image. I liked how you described the impact of each mutation explicitly such as in Albinism “ganglion cells of retina decreased by 25%”. This really helps the reader to understand the extent of the abnormalities from certain gene mutations.

3. Ocular manifestations: the opening sentence is slightly vague. Could you please state which two separate sections that you are referring to? The section that follows could be better organised. It seems to jump from genetic issues to a research timeline then to future research on that disease to another example of a genetic mutation which produces abnormalities. I would suggest putting the research timeline shortly after the introduction and integrating research history not just on LCA but other abnormalities as well. However, the content for all these sections is well referenced and interesting to read. The balance between text and images between LCA and anopthalmia/micropthalmia sections is good and are both really interesting to read! I liked how you provided some epidemiological data and clinical manifestations in depth accompanied by suitable images. However, the environmental abnormalities section could use with more dot-point styles and images to enhance the presentation and aid in your descriptions.

In regards to peer teaching (outcome 5), this page was an absolute joy to read and all technical language was explained in the glossary. Just make sure to pay attention to those minor improvements. Good job!"

====Hearing====

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

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

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

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

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

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

===Lab 9 Assessment===

====Embryonic Blood Flow and Oxygen and the Developing Pancreas====

''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.''

A study by Shah et al.<ref name="PMID21050843"><pubmed>21050843</pubmed></ref> sought to investigate whether enhanced blood flow and oxygen in a developing mouse pancreas correlates with changes in differentiation during embryonic pancreatic development. This investigation was prompted because "there is a fundamental lack of understanding of how organs in early mammalian embryos are able to form despite receiving little or no blood flow" according to Shah et al.

The methods involved injecting fluorescein-conjugated tomato lectin (a vascular tracer) into the hearts of developing mouse embryos ''in utero'' at different stages of development, guided by ultrasound backscatter microscopy. The vascular tracer was left to circulate for 10 minutes and then the mice embryos were harvested for analysis of blood flow and oxygenation. One key finding discovered through immunohistochemistry was that the developing pancreas had dense vascularity, though numerous vessels early in gestation were non-perfused. Vessels that were not perfused with blood did not induce differentiation of adjacent pancreatic epithelium. In contrast, vessels perfused with blood were surrounded by glucagon-positive and insulin-positive cells; these are indications of pancreatic cell differentiation. However, ''in vitro'' it was found that the hypoxic embryonic pancreas shows proliferation but not differentiation. Interestingly, the endocrine areas tended to be areas with flow and higher oxygenation compared to the exocrine areas of the pancreas. Moreover, later embryonic stages when global pancreatic perfusion occurred correlated with a rapid increase in exocrine differentiation. Overall, Shah et al. concluded that vascular flow with oxygenated blood, as opposed to just vascular endothelium alone, may provide specific signals for pancreatic differentiation in the early embryo.

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

Through the interaction between the neural crest and the ectoderm, 10 teeth buds form in the the embryo on in the early embryo<ref>Universities of Fribourg, Lausanne and Bern. (2012). ''Development of the Teeth''. Retrieved from http://www.embryology.ch/anglais/sdigestive/gesicht05.html</ref>. Each tooth bud has an outer area of ectodermal orgign (the enamel organ) with an inner area of dental pulp made up of solidified mesenchyme of neuroectodermal origin. The neuroectodermal mesenchyme also forms the dental follicle from which the periodontium and cement of the tooth root arise.

* '''Ectoderm''' of the oral cavity produces:
** Ameloblasts which produce the teeth enamel in the direction of the tooth pulp.
* Surrounding '''mesoderm''' (mesenchyme) in conjunction with '''neural crest''' produces:
** Odontoblasts excrete predentin below the ameloblast layer; dentin then arises through calcium salt deposition in the predentin.
** Cementoblasts in the root of the tooth produce cement.

'''References'''
<references/>

===Lab 11 Assessment===

''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.''

The CCCTC-binding factor, CTCF, has been shown in the past to be involved in transcriptional control and chromatin interactions within the cell’s nucleus<ref name="PMID20020479"><pubmed>20020479</pubmed></ref>. A recent study by Hiroseu et al. <ref name="PMID22340434"><pubmed>22340434</pubmed></ref> sought to analyse the role of CTCF in induced pluripotent stem cells (iPS) by examining three cell lines: iPS cells induced from fibroblasts (201B7), human diploid fibroblasts (IMR90) and IMR90 cells undergoing oncongene-induced senescence (OIS) after Ras activation.

Hiroseu et al. noticed that CTCF mRNA was up-regulated in the iPS cells and down-regulated in the OIS cells in comparison to the IMR90 cells<ref name="PMID22340434"/>. Similarly, high levels of CTCF protein were expressed in the iPS cells whilst the OIS cells showed little CTCF protein expression <ref name="PMID 22340434"/>. In order to clarify these results, Hiroseu et al. studied the interaction between CTCF and the and the INK4/ARF locus which encodes p15INK4b, p16INK4a and ARF: reprogramming regulators in the cell cycle which induce senescence<ref name="PMID19668188"><pubmed>19668188</pubmed></ref>. Using genome wide assay as well as CTCF binding profiles from data from past experiements, Hiroseu et al. where able to identify three CTCF enriched sites in the INK4/ARF locus: IC1, IC2 and IC3<ref name="PMID 22340434"/>. These findings are of significance as they suggest a relationship between CTCF function and INK4/ARF transcription.

Chromatin precipitation showed that CTCF could bind to IC1, IC2 and IC3 in all three cell lines<ref name="PMID 22340434"/>. The affinity of CTCF binding was found to be significantly high in the iPS cells compared to IMR90 cells<ref name="PMID 22340434"/>. Additionally, chromosome conformation capture assay showed that in both the iPS cells and IMR90 cells, p15INK4b, p16INK4a and ARF were silenced<ref name="PMID 22340434"/>. In contrast, the OIS cells showed weak CTCF binding with increased expression of p15INK4b and p16INK4a<ref name="PMID 22340434"/>. Data analysis uncovered that the inverse relationships of expression are a result of the interaction between the CTCF enriched sites and the , p15INK4b, p16INK4a and ARF promoters<ref name="PMID 22340434"/>. IC1 and IC2 strongly interacted with the p15INK4b and ARF promoters respectively<ref name="PMID 22340434"/>. Moreovereover, the IC1/ p15INK4band IC2/ARF “binding site-promotor complexes”, the p16INK4a promoter and IC3 were found to be colocalised in the nucleus; Hiroseu et al. suggested that these gene interactions involve the formation of chromosome loops in the INK4/ARG locus<ref name="PMID 22340434"/>. This hypothesis was supported by CTCF knockdown which was found to decrease the colocalisation of the genes, leading to a looser chromatin formation; this was coupled with increased expression of p15INK4b, p16INK4a <ref name="PMID 22340434"/>. From these findings, Hiroeu et al. drew the conclusion that the CTCF complex is important for compact chromatin formation at the INK4/ARF locus<ref name="PMID 22340434"/>.

In OIS cells, chromatin was found to undergo active decompaction which was related to its senescence as it allowed the expression of p15INK4b and p16INK4a<ref name="PMID 22340434"/>. In contast, repressive compaction and intermediate compaction was demonstrated in the IMR90 and iPS cells respectively, explaining the silencing of the genes in the INK4/ARF locus<ref name="PMID 22340434"/>. The implications of these findings for iPS research are two fold. Firstly, that CTCF is crucial for higher-order chromatin organization in the INK4/ARF locus in a reprogrammed cell<ref name="PMID 22340434"/>. Additionally, the chromatin decompation in the INK4/ARF locus shown in the OIS cells coupled with induction of the INK4 genes and senescence-associated nuclear changes may be a barrier for reprogramming to iPS cells<ref name="PMID 22340434"/><ref name="PMID19668188"/>.

'''References'''
<references/>

==Lab Attendance==
Lab 1 --[[User:Z3333038|Z3333038]] 11:49, 25 July 2012 (EST)

Lab 2 --[[User:Z3333038|Z3333038]] 10:05, 1 August 2012 (EST)

Lab 3 --[[User:Z3333038|Z3333038]] 10:01, 8 August 2012 (EST)

Lab 4 --[[User:Z3333038|Z3333038]] 10:00, 15 August 2012 (EST)

Lab 5 --[[User:Z3333038|Z3333038]] 09:59, 22 August 2012 (EST)

Lab 6 --[[User:Z3333038|Z3333038]] 10:10, 29 August 2012 (EST)

Lab 7 --[[User:Z3333038|Z3333038]] 10:09, 12 September 2012 (EST)

Lab 8 --[[User:Z3333038|Z3333038]] 10:00, 19 September 2012 (EST)

Lab 9 --[[User:Z3333038|Z3333038]] 10:03, 26 September 2012 (EST)

Lab 10 --[[User:Z3333038|Z3333038]] 10:04, 3 October 2012 (EST)

Lab 11 --[[User:Z3333038|Z3333038]] 10:18, 10 October 2012 (EST)

User:Z3333038

2012-10-09T23:18:51Z

Z3333038: /* Lab Attendance */

==Individual Assessments==

===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 History of In Vitro Fertilisation====
In vitro fertilisation (IVF) refers to the process of artificial fertilisation conducted ex vivo. The IVF technique was first described for non-human use. The earliest known research conducted was by Walter Heape from Cambridge University in the 1890s who reported the first known case of embryo transplantation in rabbits. In 1959, Dr. Min Chueh Chang published his work in Nature describing the first successful mammalian live birth (rabbits) after IVF therapy.

Eventually, the use of IVF for humans became a possibility and then a reality: in 1978, the first successful birth from IVF occurred in England. The success of this IVF birth is credited to Patrick Steptoe and Robert Edwards. In 2010, Edwards was awarded the [http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/ Nobel Prize in Medicine] for the development of human IVF therapy. Because of IVF, many couples have been given a chance to conceive. However, the [http://www.ivf-worldwide.com/ivf-history.html/ history of IVF] is still in the making with constant improvements in the technology being developed and applied.

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

====Research in Fertilisation====

In order for fusion between mammalian gametes to occur, a spermatozoon must first pass through the external layers surrounding the oocyte: the cumulus oophorus and the zona pellucida (ZP). It is believe that the acromosome reaction (AR) of the spermatozoa starts upon contact with the zona pellucida. Consequently, the cumulus cell layer is typically removed in studies of mouse sperm-oocyte interactions in order to facilitate fertilisation. The recent experiments of Jin et al. <ref name="PMID21383182"><pubmed>21383182</pubmed></ref> sought to answer the question: "Where does the fertilising mouse spermatozoon begin the AR - in the cumulus [of the oocyte] or the zona pellucida?" Jin et al. <ref name="PMID21383182"/> utilised fluorescence microscopy and transgenic mouse spermatozoa to conduct their investigation. Additionally, Jin et al. <ref name="PMID21383182"/> used cumulus-free oocytes and cumulus-enclosed oocytes to study the role of the cumulus cells in fertilisation.

From the experiment, Jin et al. <ref name="PMID21383182"/> found that most fertilising spermatozoa begin the AR before their first contact with the ZP. The significance of this finding was that the spermatozoa with intact acromosomes at the ZP seldom had the ability to penetrate through <ref name="PMID21383182"/>. In contrast, spermatozoa which had already began the AR could easily penetrate the ZP. In regards to the role of the cumulus cells, it was found that cumulus-enclosed oocytes had a higher incidence of fertilisation compared to cumulus-free oocytes <ref name="PMID21383182"/>. Moreover, cumulus-free oocytes had an increased incidence of in vitro fertilisation when incubated with other cumulus-enclosed cells; this finding suggests that cumulus cells harbour an important role in fertilisation <ref name="PMID21383182"/>. However, it is notable that when cumulus-free oocytes were incubated in a cumulus-conditioned medium, no increase in fertilisation rate was noted<ref name="PMID21383182"/>. Overall, two conclusions were made: firstly, that the AR is required by the spermatozoa prior to meeting the ZP for effective fertilisation<ref name="PMID21383182"/>. Secondly, the cumulus oophorus confers benefit in increasing the chance of fertilisation<ref name="PMID21383182"/>.

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 16:58, 11 September 2012 (EST) Question 1 is answered well and linked to appropriate resources. Question 2 is also quite a complete answer to what I requested. The formatting of your description could have been better organised, while it is correct to cite the paper when referring to the findings, this is a little overboard with 9 times within 2 paragraphs. If you had organised the information differently this could have been reduced to 1-2 citations within the text. Alternatively the findings could have been provided as a bullet or numbered list. '''10/10'''

===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.''
====Patterns of ZPC Deposition in Porcine Oocyte-Cumulus Complexes====
[[File:Patterns_of_ZPC_Deposition_in_Porcine_Oocytes.jpg‎]]

Immunofluorescence Detection for ZPC and Ubiquitin in a Porcine Oocyte <ref name="PMID21383844"><pubmed>21383844</pubmed></ref>

'''References'''
<references/>

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

Trophinin is a membrane protein expressed in chorionic villi trophoblasts and in the maternal endometrium. In the early stages of pregnancy, trophinin is strongly expressed along with tastin and bystin, which form a complex; this complex mediates apical cell adhesion between the trophoblasts and the endometrial epithelial cells<ref name="PMID14633596"><pubmed>14633596</pubmed></ref>. The time frame in which trophinin is expressed on the apical aspect of the endometrial cells coincides with the "implantation window"<ref name="PMID14633596"/>; the period in which successful implantation is possible. Trophonin-trophonin adhesion during implantation occurs via signal transduction with bystin and tastin<ref name="PMID22201876"><pubmed>22201876</pubmed></ref>. As a consequence of trophinin-trophinin adhesion, trophectoderm cells become activated for implantation<ref name="PMID22201876"/>. Moreover, there have been reports that endometrial epithelial cells undergo apoptosis upon blastocyst adhesion; human trophoectoderm cells express the Fas ligand which interacts with Fas expressed on the endometrium<ref name="PMID22201876"/>. However, other studies have shown that trophinin-mediated cell adhesion can induce endometrial cell apoptosis through mechanisms other than the Fas/FasL cascade<ref name="PMID22201876"/>.

In regards to ectopic pregnancies located within the fallopian tube, research has shown that trophinin is strongly expressed by both the embryonic trophoblasts and maternal fallopian tube epithelium, induced by human chorionic gonadotrophin (hCG)<ref name="PMID14633596"/>. These findings highlight the function of trophonin in facilitating implantation in conjunction with its role in the pathogenesis of ectopic pregnancies.

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 17:04, 11 September 2012 (EST) Question 1 image has been correctly uploaded and contains all the requested information in the summary box. Question 2 is a good description of this recent paper on trophinin and Implantation. '''10/10'''

===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.''
====Gestational Age versus Post-Fertilisation Age====

Gestation is the period of time between conception and birth (Kaneshiro, 2011; Vishton, 2011). Gestational age is the developmental age of the conceptus based on the presumed first day of the last normal menstrual period to the current date, measured in weeks (Kaneshiro, 2011; Vishton, 2011). In contrast, post-fertilisation age refers to the age of the conceptus expressed in elapsed time since fertilisation (Vishton, 2011). Gestational age is approximately two weeks greater than post-fertilization age (Kaneshiro, 2011; Vishton, 2011). Gestational age is used in human development because its start date can be determined by asking the mother when was the presumed first day of the last normal menstrual period (Kaneshiro, 2011; Vishton, 2011). In contrast, the moment of fertilization must be inferred (Vishton, 2011).

'''References'''

Kaneshiro, N. K. (2011). ''Gestational age''. Retrieved from http://www.umm.edu/ency/article/002367.htm

Vishton, P. M. (2011). ''Embryo Foetus Development Stages''. Retrieved from http://www.livestrong.com/article/92683-embryo-fetus-development-stages/

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

====Tissues Derived From Somites====

'''1. Bone (Sclerotome)'''

Bone tissue consists of cells separated by an extracellular matrix with organic and inorganic components (Marieb, Wilhem & Mallatt, 2010). The organic components of bone consists of cells, collagen fibres and ground substance. The cells include osteoprogenitor cells which give rise to osteoblasts: the producers of new bone matrix (osteoid). Mature osteoblasts, called osteocytes, are trapped in lacunae where they maintain the mature bone; osteocytes may revert to osteoblasts in the incidence of a fracture. Osteoclasts are multinucleated cells with ruffled plasma membrane borders and are involved in bone resorption. Bone resorption is important for bone remodelling to improve tensile strength as well as remodel the newly deposited woven bone into mature bone after a fracture. There are two types of mature (lamellar) bone: compact bone and spongy bone (Marieb et al., 2010). The compact bone occurs towards the periphery and is arranged in Haversian systems: lamellae concentrically arranged around a central Haversian canal containing blood vessels, nerves and osteocytes (Marieb et al., 2010). The different Haversian systems communicate with each other, the periosteum and endosteum through the Volkmann's canals. In contrast, spongy bone in the mature adult appears towards the centre of the diaphysis and metaphysis and is arranged in bony shelves (trabeculae) (Marieb et al., 2010). The gross porous arrangement of spongy bone is important for housing the bone marrow (Marieb et al., 2010)

'''2. The Skin (Dermotome)'''

a. ''Dermis'': The dermis is made up of two main regions: (1) the superficial papillary layer and (2) the deeper reticular layer (Marieb et al., 2010). The superficial papillary layer makes up 20% of the dermis and is areolar connective tissue consisting of collagen and elastic fibres; it includes the dermal papillae which extend into the overlying epidermis to strengthen the dermal-epidermal junction and increase surface area for nutrient, gas and waste exchange with the avascular epidermis (Marieb et al., 2010). The reticular layer is composed of dense irregular connective tissue with thick bundles of collagen and elastic fibres arranged in different planes (Marieb et al., 2010). Other cells interspersed among the connective tissue of the dermis include fibroblasts, macrophages, mast cells and other white blood cells including lymphocytes(Marieb et al., 2010). The dermis is highly vascular and supplied with nerve fibres (Marieb et al., 2010). There are two vascular plexuses; the deep dermal plexus and the subpapillary plexus (Marieb et al., 2010). These vessels serve not only for nutrient supply to the dermis and epidermis, but for temperature regulation as well (Marieb et al., 2010).

b. ''Hypodermis'': The subcutaneous layer, or fatty hypodermis, consists of areolar and adipose connective tissue(Marieb et al., 2010). The cellular components include adipocytes as well as white blood cells (Marieb et al., 2010). The hypodermis serves to store fat and anchor the skin to underlying structure in a manner that the skin can slide over structures(Marieb et al., 2010). Additionally, the adipose in the hypodermis serves an insulator.

'''3. Skeletal Muscle (Myotome)'''
Skeletal muscle fibres come together to form a larger skeletal muscle surrounded by different levels of connective tissue "coats": the epimysium surrounds the whole skeletal muscle, the perimysium covers each fascicle and the loose CT endomysium separates each skeletal muscle fibre (Marieb et al., 2010). The skeletal muscle fibres are long cylindrical cells with a diameter between 10-100um (Marieb et al., 2010) . These muscle fbres are formed by the fusion of embryonic cells and hence contain many nuclei which are located at the periphery of each fibre beneath the sarcolemma, the skeletal muscle cell membrane (Marieb et al., 2010). These muscle fibres appear striated because of the internal organelles of the muscle fibres: myofibrils, the contractile organelles of muscle tissue (Marieb et al., 2010).

'''References'''

Marieb, E. N., Wilhelm, P. B., Mallatt, J. (2010). ''Human Anatomy'' (6th ed.). San Francisco, CA: Pearson Education, Inc.

--[[User:Z8600021|Mark Hill]] 17:10, 11 September 2012 (EST) Question 1 Clearly identified and cited the difference between "gestational age" and "post-fertilisation age". Question 2 you have also identified histological descriptions at least 3 different types of tissues formed from somites. For both questions you could have formatted the references and the reference list by using the <nowiki><ref></ref></nowiki> tags and simply inserted any text that you wanted in your list between the tags. '''10/10'''

===Lab 4 Assessment===

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

*'''Amniocentesis''' <ref>Moore, K. L., Persaud, T. V. N. & Torchia, M. G. (2013). ''The Developing Human'' (9th ed.). Philadelphia, PA: Elsevier Saunders. </ref>: Amniocentesis refers to sampling of the amniotic fluid by inserting a needle through the mother's anterior abdominal and uterine walls into the amniotic cavity by piercing the chorion and amnion. This technique is performed at 15 and 18 weeks gestation. Amniocentesis is often used to detect genetic disorders as it allows for chromosome analysis. One abnormality which can be detected is trisomy 21 (Down's Syndrome)[1]. Additionally, amniocentesis can be utilised for alpha-fetoprotein assays to detect neural tube defects like spina bifida [1].

*'''Chorionic Villus Sampling''' [1]: Biopsies of trophoblastic tissue are obtained by inserting a needle through the mother's abdominal wall and uterine walls to the uterine cavity. Sampling can also be performed through the cervix with a polyethylene catheter, guided by real-time ultrasonography. CVS can be performed sooner than amniocentesis at 10 and 12 weeks of gestation. However, the rate of miscarriage from CVS is higher than amniocentesis. Like amniocentesis, CVS can be used to detect chromosomal abnormalities like trisomy 21 as well as trisomy 18. Additionally, Tay-Sachs disease can be detected with CVS [1].

====The Therapeutic Use of Cord Stem Cells====
''2. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.''

Fu et al. (2006) sought to isolate human umbilical cord mesenchymal stem cells (HUCMSCs) and transform them into dopaminergic neurons in vitro <ref name="PMID16099997"><pubmed>16099997</pubmed></ref>. The experiment was carried out in the interest of finding a potential cure for Parkinson's disease from HUCMSCs [2]. The procedure involved isolating human mesenchymal stem cells from Wharton's jelly of the umbilical cord and culturing the HUCMSCs in a neuronal conditioned medium (NCM) [2]. The differentiation of the HUCMSCs into dopaminergic neurons was induced through stepwise culturing with the NCM, sonic hedgehog and FGF-8 [2]. The successfully transformed HUCMSCs into dopaminergic neurons were selected by positive immunohistochemistry staining for tyrosine hydroxylase (TH), the rate-limiting catecholaminergic synthesizing enzyme, and dopamine secretion [2]. These neurons were then transplanted into the striatum of rats with induced Parkinson's disease by unilateral striatal lesioning with neurotoxin (6-hydroxydopamine hydrogen chloride)[2]. The effects of stem cell transplantation were examined in the Parkinsonian animals by quantification of rotations in the mice in response to amphetamine at 0, 1, 2, 3 and 4 months [2].

Despite a success rate of 12.7% of transformed HUCMSCs, the study found that the original number of HUCMSCs doubled after 3 days of culture [2]. Additionally, the transformed HUCMSCs were still viable in the rats 4 months post-transplantation without the need for immunosuppression [2]. These findings highlight HUCMSCs as a potentially safe source of organs due to their viability post-surgery and the lack of a negative host response to the newly transplanted tissues. Additionally, positive TH staining showed migration of the transformed HUCMSCs rostrally and caudally from the location of implantation [2]. Hence, the transformed HUMSCs were able to integrate properly into the patient (Parkinsonian mouse), putting forth their suitability as a tissue source for transplantation.

The clinical effects of the HUCMSCs on the Parkinsonian mice were assessed by comparing test subjects to two control groups. The first control group consisted of normal, non-Parkinsonian mice with a low score of rotation in response to amphetamine. The second control group contained Parkinsonian mice which received no treatment and had a high rotation score [2]. It was found that the second control group showed no improvement in rotation score and deteriorated further over time. Similarly, mice treated with non-transformed HUCMSCs did not have observable improvements and had a similar deteriorating rotation score to the untreated Parkinsonian animals [2]. This finding highlights that untransformed HUCMSCs confer no clinical benefit in the setting of simulated Parkinson's disease [2]. The Parkinsonian mice treated with transformed HUCMSCs at first had no observable improvement but over time showed significantly improved rotational scores relative to the Parkinsonian control group [2]. However, the transformed HUCMSCs group did not show improvement to the extent of returning to a normal level (non-Parkinsonian rat). These findings suggest that HUCMSCs could be a potential stem cell source for transplantation, however, the procedures for HUMSCs transformation and transplantation must first be reviewed [2]. Fu et al. (2006) suggested that, the number of dopaminergic neurons of implanted cells may have been relatively inadequate to alleviate the Parkinsonism symptoms in the affected rats. Additionally, the transplanted cells may take time to integrate into the host brain: only two rats in the transformed HUCMSCs group survived for at least 8 months, with amphetamine-induced rotation behavior remaining similar to that 4 months after transplantation. Hence, in order to properly assess HUCMSCs to treat Parkinson's disease, the long-term effects of transplantation must be studied [2].

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 17:18, 11 September 2012 (EST) Question 1 well answered in terms of technique and specific abnormalities. Question 2 human umbilical cord mesenchymal stem cells in Wharton's jelly have been used in several studies as potential sources of therapeutic cells. Perhaps a more recent paper next time. '''10/10'''

===Lab 7 Assessment===

====Muscle Satellite Cells====

''1. (a) Provide a one sentence definition of a muscle satellite cell''

Satellite cells are quiescent cells located beneath the basal lamina of each myofibre and function as myogenic precursors (stem cells) for postnatal muscle growth and repair <ref name="PMID16051152"><pubmed>16051152</pubmed></ref>.

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

Muscle satellite cells are at rest (G0) when skeletal muscle is not active<ref name="PMID22649641"><pubmed>22649641</pubmed></ref>. Activation can occur in the settings of physical activity and mechanical trauma <ref name="PMID12892408"/>. When satellite cells are activated, they proliferate and are converted to myoblasts which further differentiate and fuse with existing muscle fibres or form new fibres <ref name="PMID12892408"><pubmed>12892408</pubmed></ref>. The myonuclei accumulated in the tissue are of key importance for myogenesis: they aid in increasing protein synthesis and enable muscle growth (hypertrophy and hyperplasia) and regeneration<ref name="PMID16051152"/>. Without satellite cells, mature muscle fibres are unable to undergo regeneration <ref name="PMID16051152"/>. There is much speculation as to the exact mechanisms and factors which activate muscle satellite cells. It is proposed that strenuous exercise, mechanical muscle injury or myodegenerative disease result in the inflammatory response which recruits neutrophils and macrophages to the area of damage; the inflammatory mediators released in conjunction with growth factors secreted by the myofibres promote myosatellite activation <ref name="PMID12892408"/>. One proposed "triggering agent" is the production of sphingosine-1-phosphate from the inner part of the plasma membrane leading to satellite cell entry into the cell cycle <ref name="PMID17996437"><pubmed>17996437</pubmed></ref>. Additionally, mechanical stretch to the muscle fibre has been shown to trigger intracellular signals, such as nitric oxide synthesis which results in hepatocyte growth factor (HGF) release <ref name="PMID17996437"/>. Nitric oxide also induces follistatin, a fusigenic secreted molecule, which is an antagonist to myostatin. Myostatin is expressed by quiescent satellite cells and exerts a negative effect on satellite cell activation <ref name="PMID17996437"/>. IGF-IEa and MGF have also been implicated in satellite cell activation: Hill et al. (2003) demonstrated that these mediators are produced by active muscle in rodents and appear to be positive regulators of muscle hypertrophy<ref name="PMID12892408"><pubmed>12892408</pubmed></ref>. However, whilst MGF is acutely induced and is said to precede satellite cell activation, IGF-IEa has a delayed effect involved in the later phase of regeneration<ref name="PMID12892408"/>. Interestingly, in dystrophic muscles MGF is not produced, suggesting the importance of effective muscle repair to avoid the pathogenesis of muscular dystrophy syndromes <ref name="PMID12892408"/>.

Once activated, the satellite cells migrate out of the basal lamina and enter the cell cycle with coexpression of Pax7 and MyoD <ref name="PMID17996437"/>. This process occurs in conjunction with the Notch signaling pathway<ref name="PMID22493066"><pubmed>22493066</pubmed></ref>. The skeletal myoblasts that are produced divide, express myogenin and downregulate Pax7 then fuse to form myofibres<ref name="PMID17996437"/>.

====The Effects of Motor Nerve Damage on Skeletal Muscle====

''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?''

Chronic spinal cord injury (SCI) affects muscles below the level of the lesion. In terms of fibre type, one review <ref name="PMID19705475"><pubmed>19705475</pubmed></ref>describes the progressive change in fibre type toward faster phenotypes. The fibre phenotype is classified according to its myosin heavy chain (MHC) molecule which is an actin-based motor protein associated with muscle fibre contraction<ref name="PMID19705475"/>. These three MHC isoforms are MHC I, MHC IIa, and MHC IIx <ref name="PMID19705475"/>. In SCI there is a reduction of type I fibres (slow) and upregulation of type IIA and IIX fibres (fast)<ref name="PMID19705475"/>. The metabolism of the fast fibres is characterised by a predominantly anaerobic metabolism with fewer mitochondria, unlike type I fibres which undergo aerobic metabolism <ref name="PMID19705475"/>. This is in part due to a reduction in absolute activities of the muscle metabolic enzymes in SCI, favouring the fast glycolytic/oxidative type which fatigue more easily <ref name="PMID19705475"/>.

In terms of fibre size, a study by Castro et al. (1998) <ref name="PMID9887150"><pubmed>9887150</pubmed></ref> found that all fibre types underwent significant atrophy and decreased in size from the 6th to 24th week after injury<ref name="PMID9887150"/>. Moreover, average fibre cross-sectional area decreased by 22% by the 6th week post-injury <ref name="PMID9887150"/>. The changes were accompanied by either complete paralysis or loss of force with increased susceptibility to fatigue depending on the extent of injury <ref name="PMID9887150"/>. Note that whilst type II fibre atrophy is seen during the first months after complete SCI, type I fibres undergo atrophy in the later stages <ref name="PMID19705475"><pubmed>19705475</pubmed></ref>.

Interestingly, the level of the motor neuron lesion can affect the outcome of the muscle atrophy: a study by Stilwill and Sagha <ref name="PMID66912"><pubmed>66912</pubmed></ref>found that lower motor neuron lesions led to muscle fibre grouped atrophy and fibre-type grouping, whereas upper motor neuron lesions led to preferential atrophy of type II fibers with fibre-type grouping.

'''References'''
<references/>

===Lab 8 Assessment===
1. Each student should now look at each of the other Group projects in the class.

2. Next prepare a critical assessment (should include both positive and negative issues) of each project using the project assessment criteria.

3. This assessment should be pasted without signature on the top of the specific project's discussion page. (minimum length 3-5 paragraphs/project)

4. This critical assessment should also be pasted on your own student page. Each student should therefore have 5 separate reports pasted on their own page for this assessment item. Length, quality and accuracy of your reports will be part of the overall mark for this assessment (there will be a greater loading on this than simple question assessments).

====Vision====
In regards to the information presented (outcomes 1 and 9), as the project is still in progress it is understandable that some areas are incomplete. There is so far good, concise information on the structure of the development of the eye and the structures involved in vision. It would be useful to include information on the genetic factors involved in vision development as well as have a section explaining the processes involved with vision. Also, for the Current Research section (outcome 5), it would be better to explain the aims and findings of the research papers cited rather than just referencing the papers and images without describing their significance to research progress. In terms of peer teaching (outcome 4), the page contains a good balance between technical terms and simple language for understanding on the development of structures for vision; additionally, the inclusion Glossary helps to clarify any technical terms.

The most striking part of the layout (outcome 2) is the use of images to demonstrate the development of structures involved in vision. This is great because it makes the page interesting and provides a visual understanding on the development of the eye. However, at times the images could be better placed: for example, in the introduction the pictures appear stacked on top of one another. Additionally, the images in the introduction show similar structures, so perhaps select only one to better aid the flow and appearance of the page. Throughout the page, the images utilised could be provided with more description and linked to the text in order to improve flow and enhance written explanation. Perhaps some information, such as the timeline, could be sorted into a table to improve the layout.

In regards to outcome 3, some of the information provided (e.g. in the section on Development) is not referenced. Additionally, some of the references in the Reference list need to be formatted correctly with author, date, title of the page, publisher (if required) and any other necessary information. It would be useful to follow the style of the automatic default referencing.
Hope the feedback helps and all the best with your project!

====Somatosensory====
The introduction is good in that there is a description of the role of somatosensory functions as well as an overview of its development. To improve further, perhaps avoid trailing off in the final sentence and perhaps put something that concludes your introduction.

In regards to the information presented and layout (outcomes 1, 2, 4 and 9), the history of discoveries is very brief and requires more research. Additionally, it would be useful to set up a timeline to add interest. The section on the central somatosensory differentiation appeared very well researched with a very interesting picture to accompany the text – good work. The section on Touch would better be placed in a table and have accompanying images to avoid getting too ‘wordy’. Also, this section does not have any consistent referencing in the bulk of the content – please cite where you find your information. The section on pain is well researched and has a strong content, however, to enhance this section I would suggest using dot points to describe the different fibres and add a relevant image. Similarly, the hot/cold and pressure sections were great in terms of content but could use with some dot points and visual explanation to make the page more interesting. Just a note on pressure – avoid getting repetitive; the page had already defined the Ruffini’s endings/corpuscles etc in the section of Touch. Additionally, the 2 urls at the bottom of this section are distracting, make sure to incorporate these in your reference list of add them to an ‘External Links’ section. Your Current Research section requires some proof reading and additional articles to make it more comprehensive. However, you have referenced the image well and referred to it in the accompanying text.

In terms of referencing, I noticed some areas where the in-text references were not correctly formatted and were in the (Author, date) style. Perhaps have a look at the referencing tutorial on the Embryology ‘Students’ page to get an understanding of the codes required for citations. For peer teaching (outcome 4), make sure that you define all technical terms – your Glossary only has 2 definitions provided. Other than this, the content overall is interesting to read just make sure you are striking a balance between images and text. Hope it helps and all the best!

====Taste====

In regards to the information presented (outcomes 1 and 9), the timeline for the development is good and written with clarity. However, I noticed the section on structure only referred to the adult state rather than focusing on the embryonic origin of each structure (ectoderm, endoderm and mesoderm). I would suggest that you elaborate on the developmental stages introduced in the timeline in order to build on the information you have already provided. This is important in regards to outcome 6 so that you can relate your research to embryology – the development of taste should be your focus. The history timeline was great to read as it was very concise and clear.

The page shows a good level of peer teaching with clear language and a good balance between images and text (outcome 4) with technical terms explained in the glossary. An improvement could be to make a link between any technical language and the glossary to avoid scrolling up and down to the page. Your Current Research section (outcome 5) was very interesting to read and showed you went beyond the scope of basic research on taste – good work!

In terms of layout (outcome 2), whilst the images are interesting and relevant to the text, some are not appropriately referenced nor described; make sure to reference appropriately and at least write one or two sentences to make the images relevant to the reader. Additionally, the introduction should not be under another subheading (Gustatory system) as it creates some confusion; I would suggest making the introduction its own heading in order to make the page flow. Similarly, the history timeline would best be placed towards the beginning of the page, under the introduction.

I noticed some areas (such as the section on Structure) were not appropriately or consistently referenced. Make sure to include a citation anytime you introduce a researched idea or information to avoid being accused of plagiarism. I noticed the history timeline had good consistent referencing; however the numbers just need to be formatted so they come under the reference list. If you click on the Tutorial: References page linked from the student page, it tells you how to do this. Hope the feedback helps and all the best for your project!

====Abnormal Vision====
"The introduction is good in the manner that it provides some brief background information regarding the normal development of the eye and abnormalities. Additionally, I liked how the introduction described the aims of the page because it sets up a structure for the reader to follow. Just make sure to proof read this section: “The development of the eye is very sensitive and REQUIRES accurate...”

In regards to the information presented and layout (outcomes 1, 2, 4 and 9):

1. Normal Eye Development: This section appears very well researched. I like how you referred to the stages throughout development. However, this section could be enhanced by adding an image of the normal eye structure and development – this acts as a reference point for your page viewers, allowing for a clear visual comparison between the abnormalities and normal structure.

2. Abnormal Development: I like the overview provided at the beginning as it sets the scene for what points you will be covering in this section. Great job. All sections are quite good, just perhaps include more images to further enhance your page.

a. Abnormal lens development: I liked how you first described the function of the gene in development and then stated any abnormalities that arise when the gene is not expressed or mutated. I liked how you included an image for the crystalline genes; just make sure to refer to the image in text (e.g. see fig. 1. or see accompanying image).

b. Abnormal corneal development: Similar to the abnormal lens section, there is a good explanation provided for each gene involved. Just some improvements: make sure to reference all information; e.g. No reference provided for “The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of....”. The accompanying image has been referenced correctly and described, good work!

c. Abnormal retinal development: Once again, a great scope of research and information and suitable image. I liked how you described the impact of each mutation explicitly such as in Albinism “ganglion cells of retina decreased by 25%”. This really helps the reader to understand the extent of the abnormalities from certain gene mutations.

3. Ocular manifestations: the opening sentence is slightly vague. Could you please state which two separate sections that you are referring to? The section that follows could be better organised. It seems to jump from genetic issues to a research timeline then to future research on that disease to another example of a genetic mutation which produces abnormalities. I would suggest putting the research timeline shortly after the introduction and integrating research history not just on LCA but other abnormalities as well. However, the content for all these sections is well referenced and interesting to read. The balance between text and images between LCA and anopthalmia/micropthalmia sections is good and are both really interesting to read! I liked how you provided some epidemiological data and clinical manifestations in depth accompanied by suitable images. However, the environmental abnormalities section could use with more dot-point styles and images to enhance the presentation and aid in your descriptions.

In regards to peer teaching (outcome 5), this page was an absolute joy to read and all technical language was explained in the glossary. Just make sure to pay attention to those minor improvements. Good job!"

====Hearing====

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

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

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

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

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

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

===Lab 9 Assessment===

====Embryonic Blood Flow and Oxygen and the Developing Pancreas====

''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.''

A study by Shah et al.<ref name="PMID21050843"><pubmed>21050843</pubmed></ref> sought to investigate whether enhanced blood flow and oxygen in a developing mouse pancreas correlates with changes in differentiation during embryonic pancreatic development. This investigation was prompted because "there is a fundamental lack of understanding of how organs in early mammalian embryos are able to form despite receiving little or no blood flow" according to Shah et al.

The methods involved injecting fluorescein-conjugated tomato lectin (a vascular tracer) into the hearts of developing mouse embryos ''in utero'' at different stages of development, guided by ultrasound backscatter microscopy. The vascular tracer was left to circulate for 10 minutes and then the mice embryos were harvested for analysis of blood flow and oxygenation. One key finding discovered through immunohistochemistry was that the developing pancreas had dense vascularity, though numerous vessels early in gestation were non-perfused. Vessels that were not perfused with blood did not induce differentiation of adjacent pancreatic epithelium. In contrast, vessels perfused with blood were surrounded by glucagon-positive and insulin-positive cells; these are indications of pancreatic cell differentiation. However, ''in vitro'' it was found that the hypoxic embryonic pancreas shows proliferation but not differentiation. Interestingly, the endocrine areas tended to be areas with flow and higher oxygenation compared to the exocrine areas of the pancreas. Moreover, later embryonic stages when global pancreatic perfusion occurred correlated with a rapid increase in exocrine differentiation. Overall, Shah et al. concluded that vascular flow with oxygenated blood, as opposed to just vascular endothelium alone, may provide specific signals for pancreatic differentiation in the early embryo.

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

Through the interaction between the neural crest and the ectoderm, 10 teeth buds form in the the embryo on in the early embryo<ref>Universities of Fribourg, Lausanne and Bern. (2012). ''Development of the Teeth''. Retrieved from http://www.embryology.ch/anglais/sdigestive/gesicht05.html</ref>. Each tooth bud has an outer area of ectodermal orgign (the enamel organ) with an inner area of dental pulp made up of solidified mesenchyme of neuroectodermal origin. The neuroectodermal mesenchyme also forms the dental follicle from which the periodontium and cement of the tooth root arise.

* '''Ectoderm''' of the oral cavity produces:
** Ameloblasts which produce the teeth enamel in the direction of the tooth pulp.
* Surrounding '''mesoderm''' (mesenchyme) in conjunction with '''neural crest''' produces:
** Odontoblasts excrete predentin below the ameloblast layer; dentin then arises through calcium salt deposition in the predentin.
** Cementoblasts in the root of the tooth produce cement.

'''References'''
<references/>

==Lab Attendance==
Lab 1 --[[User:Z3333038|Z3333038]] 11:49, 25 July 2012 (EST)

Lab 2 --[[User:Z3333038|Z3333038]] 10:05, 1 August 2012 (EST)

Lab 3 --[[User:Z3333038|Z3333038]] 10:01, 8 August 2012 (EST)

Lab 4 --[[User:Z3333038|Z3333038]] 10:00, 15 August 2012 (EST)

Lab 5 --[[User:Z3333038|Z3333038]] 09:59, 22 August 2012 (EST)

Lab 6 --[[User:Z3333038|Z3333038]] 10:10, 29 August 2012 (EST)

Lab 7 --[[User:Z3333038|Z3333038]] 10:09, 12 September 2012 (EST)

Lab 8 --[[User:Z3333038|Z3333038]] 10:00, 19 September 2012 (EST)

Lab 9 --[[User:Z3333038|Z3333038]] 10:03, 26 September 2012 (EST)

Lab 10 --[[User:Z3333038|Z3333038]] 10:04, 3 October 2012 (EST)

Lab 11 --[[User:Z3333038|Z3333038]] 10:18, 10 October 2012 (EST)

2012 Group Project 4

2012-10-03T11:00:57Z

Z3333038: /* Congenital Abnormalities */

[[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|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|300px|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 ====

[[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. 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|180px|thumb|right|Signal Transduction and Processes in Olfaction]]
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>
||
[[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.

----

{{2012Projects}}

2012 Group Project 4

2012-10-03T10:20:09Z

Z3333038: /* Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons */

[[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|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|300px|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 ====

[[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. 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|180px|thumb|right|Signal Transduction and Processes in Olfaction]]
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>
||
[[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 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 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.

----

{{2012Projects}}

2012 Group Project 4

2012-10-03T10:15:41Z

Z3333038: /* Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development */

[[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|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|300px|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 ====

[[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. 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|180px|thumb|right|Signal Transduction and Processes in Olfaction]]
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>
||
[[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 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 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===
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]

==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.

----

{{2012Projects}}

2012 Group Project 4

2012-10-03T01:06:38Z

Z3333038: /* Olfactory Signal Transduction */

[[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|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|300px|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 ====

[[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. 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|200px|thumb|right|Signal Transduction and Processes in Olfaction]]
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>
||
[[#Anatomy of the Olfactory System |'''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

2012-10-03T01:05:40Z

Z3333038: /* Olfactory Signal Transduction */

[[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|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|300px|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 ====

[[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. 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|300px|thumb|right|Signal Transduction and Processes in Olfaction]]
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>
||
[[#Anatomy of the Olfactory System |'''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}}

User:Z3333038

2012-10-03T00:04:27Z

Z3333038: /* Lab Attendance */

==Individual Assessments==

===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 History of In Vitro Fertilisation====
In vitro fertilisation (IVF) refers to the process of artificial fertilisation conducted ex vivo. The IVF technique was first described for non-human use. The earliest known research conducted was by Walter Heape from Cambridge University in the 1890s who reported the first known case of embryo transplantation in rabbits. In 1959, Dr. Min Chueh Chang published his work in Nature describing the first successful mammalian live birth (rabbits) after IVF therapy.

Eventually, the use of IVF for humans became a possibility and then a reality: in 1978, the first successful birth from IVF occurred in England. The success of this IVF birth is credited to Patrick Steptoe and Robert Edwards. In 2010, Edwards was awarded the [http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/ Nobel Prize in Medicine] for the development of human IVF therapy. Because of IVF, many couples have been given a chance to conceive. However, the [http://www.ivf-worldwide.com/ivf-history.html/ history of IVF] is still in the making with constant improvements in the technology being developed and applied.

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

====Research in Fertilisation====

In order for fusion between mammalian gametes to occur, a spermatozoon must first pass through the external layers surrounding the oocyte: the cumulus oophorus and the zona pellucida (ZP). It is believe that the acromosome reaction (AR) of the spermatozoa starts upon contact with the zona pellucida. Consequently, the cumulus cell layer is typically removed in studies of mouse sperm-oocyte interactions in order to facilitate fertilisation. The recent experiments of Jin et al. <ref name="PMID21383182"><pubmed>21383182</pubmed></ref> sought to answer the question: "Where does the fertilising mouse spermatozoon begin the AR - in the cumulus [of the oocyte] or the zona pellucida?" Jin et al. <ref name="PMID21383182"/> utilised fluorescence microscopy and transgenic mouse spermatozoa to conduct their investigation. Additionally, Jin et al. <ref name="PMID21383182"/> used cumulus-free oocytes and cumulus-enclosed oocytes to study the role of the cumulus cells in fertilisation.

From the experiment, Jin et al. <ref name="PMID21383182"/> found that most fertilising spermatozoa begin the AR before their first contact with the ZP. The significance of this finding was that the spermatozoa with intact acromosomes at the ZP seldom had the ability to penetrate through <ref name="PMID21383182"/>. In contrast, spermatozoa which had already began the AR could easily penetrate the ZP. In regards to the role of the cumulus cells, it was found that cumulus-enclosed oocytes had a higher incidence of fertilisation compared to cumulus-free oocytes <ref name="PMID21383182"/>. Moreover, cumulus-free oocytes had an increased incidence of in vitro fertilisation when incubated with other cumulus-enclosed cells; this finding suggests that cumulus cells harbour an important role in fertilisation <ref name="PMID21383182"/>. However, it is notable that when cumulus-free oocytes were incubated in a cumulus-conditioned medium, no increase in fertilisation rate was noted<ref name="PMID21383182"/>. Overall, two conclusions were made: firstly, that the AR is required by the spermatozoa prior to meeting the ZP for effective fertilisation<ref name="PMID21383182"/>. Secondly, the cumulus oophorus confers benefit in increasing the chance of fertilisation<ref name="PMID21383182"/>.

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 16:58, 11 September 2012 (EST) Question 1 is answered well and linked to appropriate resources. Question 2 is also quite a complete answer to what I requested. The formatting of your description could have been better organised, while it is correct to cite the paper when referring to the findings, this is a little overboard with 9 times within 2 paragraphs. If you had organised the information differently this could have been reduced to 1-2 citations within the text. Alternatively the findings could have been provided as a bullet or numbered list. '''10/10'''

===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.''
====Patterns of ZPC Deposition in Porcine Oocyte-Cumulus Complexes====
[[File:Patterns_of_ZPC_Deposition_in_Porcine_Oocytes.jpg‎]]

Immunofluorescence Detection for ZPC and Ubiquitin in a Porcine Oocyte <ref name="PMID21383844"><pubmed>21383844</pubmed></ref>

'''References'''
<references/>

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

Trophinin is a membrane protein expressed in chorionic villi trophoblasts and in the maternal endometrium. In the early stages of pregnancy, trophinin is strongly expressed along with tastin and bystin, which form a complex; this complex mediates apical cell adhesion between the trophoblasts and the endometrial epithelial cells<ref name="PMID14633596"><pubmed>14633596</pubmed></ref>. The time frame in which trophinin is expressed on the apical aspect of the endometrial cells coincides with the "implantation window"<ref name="PMID14633596"/>; the period in which successful implantation is possible. Trophonin-trophonin adhesion during implantation occurs via signal transduction with bystin and tastin<ref name="PMID22201876"><pubmed>22201876</pubmed></ref>. As a consequence of trophinin-trophinin adhesion, trophectoderm cells become activated for implantation<ref name="PMID22201876"/>. Moreover, there have been reports that endometrial epithelial cells undergo apoptosis upon blastocyst adhesion; human trophoectoderm cells express the Fas ligand which interacts with Fas expressed on the endometrium<ref name="PMID22201876"/>. However, other studies have shown that trophinin-mediated cell adhesion can induce endometrial cell apoptosis through mechanisms other than the Fas/FasL cascade<ref name="PMID22201876"/>.

In regards to ectopic pregnancies located within the fallopian tube, research has shown that trophinin is strongly expressed by both the embryonic trophoblasts and maternal fallopian tube epithelium, induced by human chorionic gonadotrophin (hCG)<ref name="PMID14633596"/>. These findings highlight the function of trophonin in facilitating implantation in conjunction with its role in the pathogenesis of ectopic pregnancies.

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 17:04, 11 September 2012 (EST) Question 1 image has been correctly uploaded and contains all the requested information in the summary box. Question 2 is a good description of this recent paper on trophinin and Implantation. '''10/10'''

===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.''
====Gestational Age versus Post-Fertilisation Age====

Gestation is the period of time between conception and birth (Kaneshiro, 2011; Vishton, 2011). Gestational age is the developmental age of the conceptus based on the presumed first day of the last normal menstrual period to the current date, measured in weeks (Kaneshiro, 2011; Vishton, 2011). In contrast, post-fertilisation age refers to the age of the conceptus expressed in elapsed time since fertilisation (Vishton, 2011). Gestational age is approximately two weeks greater than post-fertilization age (Kaneshiro, 2011; Vishton, 2011). Gestational age is used in human development because its start date can be determined by asking the mother when was the presumed first day of the last normal menstrual period (Kaneshiro, 2011; Vishton, 2011). In contrast, the moment of fertilization must be inferred (Vishton, 2011).

'''References'''

Kaneshiro, N. K. (2011). ''Gestational age''. Retrieved from http://www.umm.edu/ency/article/002367.htm

Vishton, P. M. (2011). ''Embryo Foetus Development Stages''. Retrieved from http://www.livestrong.com/article/92683-embryo-fetus-development-stages/

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

====Tissues Derived From Somites====

'''1. Bone (Sclerotome)'''

Bone tissue consists of cells separated by an extracellular matrix with organic and inorganic components (Marieb, Wilhem & Mallatt, 2010). The organic components of bone consists of cells, collagen fibres and ground substance. The cells include osteoprogenitor cells which give rise to osteoblasts: the producers of new bone matrix (osteoid). Mature osteoblasts, called osteocytes, are trapped in lacunae where they maintain the mature bone; osteocytes may revert to osteoblasts in the incidence of a fracture. Osteoclasts are multinucleated cells with ruffled plasma membrane borders and are involved in bone resorption. Bone resorption is important for bone remodelling to improve tensile strength as well as remodel the newly deposited woven bone into mature bone after a fracture. There are two types of mature (lamellar) bone: compact bone and spongy bone (Marieb et al., 2010). The compact bone occurs towards the periphery and is arranged in Haversian systems: lamellae concentrically arranged around a central Haversian canal containing blood vessels, nerves and osteocytes (Marieb et al., 2010). The different Haversian systems communicate with each other, the periosteum and endosteum through the Volkmann's canals. In contrast, spongy bone in the mature adult appears towards the centre of the diaphysis and metaphysis and is arranged in bony shelves (trabeculae) (Marieb et al., 2010). The gross porous arrangement of spongy bone is important for housing the bone marrow (Marieb et al., 2010)

'''2. The Skin (Dermotome)'''

a. ''Dermis'': The dermis is made up of two main regions: (1) the superficial papillary layer and (2) the deeper reticular layer (Marieb et al., 2010). The superficial papillary layer makes up 20% of the dermis and is areolar connective tissue consisting of collagen and elastic fibres; it includes the dermal papillae which extend into the overlying epidermis to strengthen the dermal-epidermal junction and increase surface area for nutrient, gas and waste exchange with the avascular epidermis (Marieb et al., 2010). The reticular layer is composed of dense irregular connective tissue with thick bundles of collagen and elastic fibres arranged in different planes (Marieb et al., 2010). Other cells interspersed among the connective tissue of the dermis include fibroblasts, macrophages, mast cells and other white blood cells including lymphocytes(Marieb et al., 2010). The dermis is highly vascular and supplied with nerve fibres (Marieb et al., 2010). There are two vascular plexuses; the deep dermal plexus and the subpapillary plexus (Marieb et al., 2010). These vessels serve not only for nutrient supply to the dermis and epidermis, but for temperature regulation as well (Marieb et al., 2010).

b. ''Hypodermis'': The subcutaneous layer, or fatty hypodermis, consists of areolar and adipose connective tissue(Marieb et al., 2010). The cellular components include adipocytes as well as white blood cells (Marieb et al., 2010). The hypodermis serves to store fat and anchor the skin to underlying structure in a manner that the skin can slide over structures(Marieb et al., 2010). Additionally, the adipose in the hypodermis serves an insulator.

'''3. Skeletal Muscle (Myotome)'''
Skeletal muscle fibres come together to form a larger skeletal muscle surrounded by different levels of connective tissue "coats": the epimysium surrounds the whole skeletal muscle, the perimysium covers each fascicle and the loose CT endomysium separates each skeletal muscle fibre (Marieb et al., 2010). The skeletal muscle fibres are long cylindrical cells with a diameter between 10-100um (Marieb et al., 2010) . These muscle fbres are formed by the fusion of embryonic cells and hence contain many nuclei which are located at the periphery of each fibre beneath the sarcolemma, the skeletal muscle cell membrane (Marieb et al., 2010). These muscle fibres appear striated because of the internal organelles of the muscle fibres: myofibrils, the contractile organelles of muscle tissue (Marieb et al., 2010).

'''References'''

Marieb, E. N., Wilhelm, P. B., Mallatt, J. (2010). ''Human Anatomy'' (6th ed.). San Francisco, CA: Pearson Education, Inc.

--[[User:Z8600021|Mark Hill]] 17:10, 11 September 2012 (EST) Question 1 Clearly identified and cited the difference between "gestational age" and "post-fertilisation age". Question 2 you have also identified histological descriptions at least 3 different types of tissues formed from somites. For both questions you could have formatted the references and the reference list by using the <nowiki><ref></ref></nowiki> tags and simply inserted any text that you wanted in your list between the tags. '''10/10'''

===Lab 4 Assessment===

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

*'''Amniocentesis''' <ref>Moore, K. L., Persaud, T. V. N. & Torchia, M. G. (2013). ''The Developing Human'' (9th ed.). Philadelphia, PA: Elsevier Saunders. </ref>: Amniocentesis refers to sampling of the amniotic fluid by inserting a needle through the mother's anterior abdominal and uterine walls into the amniotic cavity by piercing the chorion and amnion. This technique is performed at 15 and 18 weeks gestation. Amniocentesis is often used to detect genetic disorders as it allows for chromosome analysis. One abnormality which can be detected is trisomy 21 (Down's Syndrome)[1]. Additionally, amniocentesis can be utilised for alpha-fetoprotein assays to detect neural tube defects like spina bifida [1].

*'''Chorionic Villus Sampling''' [1]: Biopsies of trophoblastic tissue are obtained by inserting a needle through the mother's abdominal wall and uterine walls to the uterine cavity. Sampling can also be performed through the cervix with a polyethylene catheter, guided by real-time ultrasonography. CVS can be performed sooner than amniocentesis at 10 and 12 weeks of gestation. However, the rate of miscarriage from CVS is higher than amniocentesis. Like amniocentesis, CVS can be used to detect chromosomal abnormalities like trisomy 21 as well as trisomy 18. Additionally, Tay-Sachs disease can be detected with CVS [1].

====The Therapeutic Use of Cord Stem Cells====
''2. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.''

Fu et al. (2006) sought to isolate human umbilical cord mesenchymal stem cells (HUCMSCs) and transform them into dopaminergic neurons in vitro <ref name="PMID16099997"><pubmed>16099997</pubmed></ref>. The experiment was carried out in the interest of finding a potential cure for Parkinson's disease from HUCMSCs [2]. The procedure involved isolating human mesenchymal stem cells from Wharton's jelly of the umbilical cord and culturing the HUCMSCs in a neuronal conditioned medium (NCM) [2]. The differentiation of the HUCMSCs into dopaminergic neurons was induced through stepwise culturing with the NCM, sonic hedgehog and FGF-8 [2]. The successfully transformed HUCMSCs into dopaminergic neurons were selected by positive immunohistochemistry staining for tyrosine hydroxylase (TH), the rate-limiting catecholaminergic synthesizing enzyme, and dopamine secretion [2]. These neurons were then transplanted into the striatum of rats with induced Parkinson's disease by unilateral striatal lesioning with neurotoxin (6-hydroxydopamine hydrogen chloride)[2]. The effects of stem cell transplantation were examined in the Parkinsonian animals by quantification of rotations in the mice in response to amphetamine at 0, 1, 2, 3 and 4 months [2].

Despite a success rate of 12.7% of transformed HUCMSCs, the study found that the original number of HUCMSCs doubled after 3 days of culture [2]. Additionally, the transformed HUCMSCs were still viable in the rats 4 months post-transplantation without the need for immunosuppression [2]. These findings highlight HUCMSCs as a potentially safe source of organs due to their viability post-surgery and the lack of a negative host response to the newly transplanted tissues. Additionally, positive TH staining showed migration of the transformed HUCMSCs rostrally and caudally from the location of implantation [2]. Hence, the transformed HUMSCs were able to integrate properly into the patient (Parkinsonian mouse), putting forth their suitability as a tissue source for transplantation.

The clinical effects of the HUCMSCs on the Parkinsonian mice were assessed by comparing test subjects to two control groups. The first control group consisted of normal, non-Parkinsonian mice with a low score of rotation in response to amphetamine. The second control group contained Parkinsonian mice which received no treatment and had a high rotation score [2]. It was found that the second control group showed no improvement in rotation score and deteriorated further over time. Similarly, mice treated with non-transformed HUCMSCs did not have observable improvements and had a similar deteriorating rotation score to the untreated Parkinsonian animals [2]. This finding highlights that untransformed HUCMSCs confer no clinical benefit in the setting of simulated Parkinson's disease [2]. The Parkinsonian mice treated with transformed HUCMSCs at first had no observable improvement but over time showed significantly improved rotational scores relative to the Parkinsonian control group [2]. However, the transformed HUCMSCs group did not show improvement to the extent of returning to a normal level (non-Parkinsonian rat). These findings suggest that HUCMSCs could be a potential stem cell source for transplantation, however, the procedures for HUMSCs transformation and transplantation must first be reviewed [2]. Fu et al. (2006) suggested that, the number of dopaminergic neurons of implanted cells may have been relatively inadequate to alleviate the Parkinsonism symptoms in the affected rats. Additionally, the transplanted cells may take time to integrate into the host brain: only two rats in the transformed HUCMSCs group survived for at least 8 months, with amphetamine-induced rotation behavior remaining similar to that 4 months after transplantation. Hence, in order to properly assess HUCMSCs to treat Parkinson's disease, the long-term effects of transplantation must be studied [2].

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 17:18, 11 September 2012 (EST) Question 1 well answered in terms of technique and specific abnormalities. Question 2 human umbilical cord mesenchymal stem cells in Wharton's jelly have been used in several studies as potential sources of therapeutic cells. Perhaps a more recent paper next time. '''10/10'''

===Lab 7 Assessment===

====Muscle Satellite Cells====

''1. (a) Provide a one sentence definition of a muscle satellite cell''

Satellite cells are quiescent cells located beneath the basal lamina of each myofibre and function as myogenic precursors (stem cells) for postnatal muscle growth and repair <ref name="PMID16051152"><pubmed>16051152</pubmed></ref>.

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

Muscle satellite cells are at rest (G0) when skeletal muscle is not active<ref name="PMID22649641"><pubmed>22649641</pubmed></ref>. Activation can occur in the settings of physical activity and mechanical trauma <ref name="PMID12892408"/>. When satellite cells are activated, they proliferate and are converted to myoblasts which further differentiate and fuse with existing muscle fibres or form new fibres <ref name="PMID12892408"><pubmed>12892408</pubmed></ref>. The myonuclei accumulated in the tissue are of key importance for myogenesis: they aid in increasing protein synthesis and enable muscle growth (hypertrophy and hyperplasia) and regeneration<ref name="PMID16051152"/>. Without satellite cells, mature muscle fibres are unable to undergo regeneration <ref name="PMID16051152"/>. There is much speculation as to the exact mechanisms and factors which activate muscle satellite cells. It is proposed that strenuous exercise, mechanical muscle injury or myodegenerative disease result in the inflammatory response which recruits neutrophils and macrophages to the area of damage; the inflammatory mediators released in conjunction with growth factors secreted by the myofibres promote myosatellite activation <ref name="PMID12892408"/>. One proposed "triggering agent" is the production of sphingosine-1-phosphate from the inner part of the plasma membrane leading to satellite cell entry into the cell cycle <ref name="PMID17996437"><pubmed>17996437</pubmed></ref>. Additionally, mechanical stretch to the muscle fibre has been shown to trigger intracellular signals, such as nitric oxide synthesis which results in hepatocyte growth factor (HGF) release <ref name="PMID17996437"/>. Nitric oxide also induces follistatin, a fusigenic secreted molecule, which is an antagonist to myostatin. Myostatin is expressed by quiescent satellite cells and exerts a negative effect on satellite cell activation <ref name="PMID17996437"/>. IGF-IEa and MGF have also been implicated in satellite cell activation: Hill et al. (2003) demonstrated that these mediators are produced by active muscle in rodents and appear to be positive regulators of muscle hypertrophy<ref name="PMID12892408"><pubmed>12892408</pubmed></ref>. However, whilst MGF is acutely induced and is said to precede satellite cell activation, IGF-IEa has a delayed effect involved in the later phase of regeneration<ref name="PMID12892408"/>. Interestingly, in dystrophic muscles MGF is not produced, suggesting the importance of effective muscle repair to avoid the pathogenesis of muscular dystrophy syndromes <ref name="PMID12892408"/>.

Once activated, the satellite cells migrate out of the basal lamina and enter the cell cycle with coexpression of Pax7 and MyoD <ref name="PMID17996437"/>. This process occurs in conjunction with the Notch signaling pathway<ref name="PMID22493066"><pubmed>22493066</pubmed></ref>. The skeletal myoblasts that are produced divide, express myogenin and downregulate Pax7 then fuse to form myofibres<ref name="PMID17996437"/>.

====The Effects of Motor Nerve Damage on Skeletal Muscle====

''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?''

Chronic spinal cord injury (SCI) affects muscles below the level of the lesion. In terms of fibre type, one review <ref name="PMID19705475"><pubmed>19705475</pubmed></ref>describes the progressive change in fibre type toward faster phenotypes. The fibre phenotype is classified according to its myosin heavy chain (MHC) molecule which is an actin-based motor protein associated with muscle fibre contraction<ref name="PMID19705475"/>. These three MHC isoforms are MHC I, MHC IIa, and MHC IIx <ref name="PMID19705475"/>. In SCI there is a reduction of type I fibres (slow) and upregulation of type IIA and IIX fibres (fast)<ref name="PMID19705475"/>. The metabolism of the fast fibres is characterised by a predominantly anaerobic metabolism with fewer mitochondria, unlike type I fibres which undergo aerobic metabolism <ref name="PMID19705475"/>. This is in part due to a reduction in absolute activities of the muscle metabolic enzymes in SCI, favouring the fast glycolytic/oxidative type which fatigue more easily <ref name="PMID19705475"/>.

In terms of fibre size, a study by Castro et al. (1998) <ref name="PMID9887150"><pubmed>9887150</pubmed></ref> found that all fibre types underwent significant atrophy and decreased in size from the 6th to 24th week after injury<ref name="PMID9887150"/>. Moreover, average fibre cross-sectional area decreased by 22% by the 6th week post-injury <ref name="PMID9887150"/>. The changes were accompanied by either complete paralysis or loss of force with increased susceptibility to fatigue depending on the extent of injury <ref name="PMID9887150"/>. Note that whilst type II fibre atrophy is seen during the first months after complete SCI, type I fibres undergo atrophy in the later stages <ref name="PMID19705475"><pubmed>19705475</pubmed></ref>.

Interestingly, the level of the motor neuron lesion can affect the outcome of the muscle atrophy: a study by Stilwill and Sagha <ref name="PMID66912"><pubmed>66912</pubmed></ref>found that lower motor neuron lesions led to muscle fibre grouped atrophy and fibre-type grouping, whereas upper motor neuron lesions led to preferential atrophy of type II fibers with fibre-type grouping.

'''References'''
<references/>

===Lab 8 Assessment===
1. Each student should now look at each of the other Group projects in the class.

2. Next prepare a critical assessment (should include both positive and negative issues) of each project using the project assessment criteria.

3. This assessment should be pasted without signature on the top of the specific project's discussion page. (minimum length 3-5 paragraphs/project)

4. This critical assessment should also be pasted on your own student page. Each student should therefore have 5 separate reports pasted on their own page for this assessment item. Length, quality and accuracy of your reports will be part of the overall mark for this assessment (there will be a greater loading on this than simple question assessments).

====Vision====
In regards to the information presented (outcomes 1 and 9), as the project is still in progress it is understandable that some areas are incomplete. There is so far good, concise information on the structure of the development of the eye and the structures involved in vision. It would be useful to include information on the genetic factors involved in vision development as well as have a section explaining the processes involved with vision. Also, for the Current Research section (outcome 5), it would be better to explain the aims and findings of the research papers cited rather than just referencing the papers and images without describing their significance to research progress. In terms of peer teaching (outcome 4), the page contains a good balance between technical terms and simple language for understanding on the development of structures for vision; additionally, the inclusion Glossary helps to clarify any technical terms.

The most striking part of the layout (outcome 2) is the use of images to demonstrate the development of structures involved in vision. This is great because it makes the page interesting and provides a visual understanding on the development of the eye. However, at times the images could be better placed: for example, in the introduction the pictures appear stacked on top of one another. Additionally, the images in the introduction show similar structures, so perhaps select only one to better aid the flow and appearance of the page. Throughout the page, the images utilised could be provided with more description and linked to the text in order to improve flow and enhance written explanation. Perhaps some information, such as the timeline, could be sorted into a table to improve the layout.

In regards to outcome 3, some of the information provided (e.g. in the section on Development) is not referenced. Additionally, some of the references in the Reference list need to be formatted correctly with author, date, title of the page, publisher (if required) and any other necessary information. It would be useful to follow the style of the automatic default referencing.
Hope the feedback helps and all the best with your project!

====Somatosensory====
The introduction is good in that there is a description of the role of somatosensory functions as well as an overview of its development. To improve further, perhaps avoid trailing off in the final sentence and perhaps put something that concludes your introduction.

In regards to the information presented and layout (outcomes 1, 2, 4 and 9), the history of discoveries is very brief and requires more research. Additionally, it would be useful to set up a timeline to add interest. The section on the central somatosensory differentiation appeared very well researched with a very interesting picture to accompany the text – good work. The section on Touch would better be placed in a table and have accompanying images to avoid getting too ‘wordy’. Also, this section does not have any consistent referencing in the bulk of the content – please cite where you find your information. The section on pain is well researched and has a strong content, however, to enhance this section I would suggest using dot points to describe the different fibres and add a relevant image. Similarly, the hot/cold and pressure sections were great in terms of content but could use with some dot points and visual explanation to make the page more interesting. Just a note on pressure – avoid getting repetitive; the page had already defined the Ruffini’s endings/corpuscles etc in the section of Touch. Additionally, the 2 urls at the bottom of this section are distracting, make sure to incorporate these in your reference list of add them to an ‘External Links’ section. Your Current Research section requires some proof reading and additional articles to make it more comprehensive. However, you have referenced the image well and referred to it in the accompanying text.

In terms of referencing, I noticed some areas where the in-text references were not correctly formatted and were in the (Author, date) style. Perhaps have a look at the referencing tutorial on the Embryology ‘Students’ page to get an understanding of the codes required for citations. For peer teaching (outcome 4), make sure that you define all technical terms – your Glossary only has 2 definitions provided. Other than this, the content overall is interesting to read just make sure you are striking a balance between images and text. Hope it helps and all the best!

====Taste====

In regards to the information presented (outcomes 1 and 9), the timeline for the development is good and written with clarity. However, I noticed the section on structure only referred to the adult state rather than focusing on the embryonic origin of each structure (ectoderm, endoderm and mesoderm). I would suggest that you elaborate on the developmental stages introduced in the timeline in order to build on the information you have already provided. This is important in regards to outcome 6 so that you can relate your research to embryology – the development of taste should be your focus. The history timeline was great to read as it was very concise and clear.

The page shows a good level of peer teaching with clear language and a good balance between images and text (outcome 4) with technical terms explained in the glossary. An improvement could be to make a link between any technical language and the glossary to avoid scrolling up and down to the page. Your Current Research section (outcome 5) was very interesting to read and showed you went beyond the scope of basic research on taste – good work!

In terms of layout (outcome 2), whilst the images are interesting and relevant to the text, some are not appropriately referenced nor described; make sure to reference appropriately and at least write one or two sentences to make the images relevant to the reader. Additionally, the introduction should not be under another subheading (Gustatory system) as it creates some confusion; I would suggest making the introduction its own heading in order to make the page flow. Similarly, the history timeline would best be placed towards the beginning of the page, under the introduction.

I noticed some areas (such as the section on Structure) were not appropriately or consistently referenced. Make sure to include a citation anytime you introduce a researched idea or information to avoid being accused of plagiarism. I noticed the history timeline had good consistent referencing; however the numbers just need to be formatted so they come under the reference list. If you click on the Tutorial: References page linked from the student page, it tells you how to do this. Hope the feedback helps and all the best for your project!

====Abnormal Vision====
"The introduction is good in the manner that it provides some brief background information regarding the normal development of the eye and abnormalities. Additionally, I liked how the introduction described the aims of the page because it sets up a structure for the reader to follow. Just make sure to proof read this section: “The development of the eye is very sensitive and REQUIRES accurate...”

In regards to the information presented and layout (outcomes 1, 2, 4 and 9):

1. Normal Eye Development: This section appears very well researched. I like how you referred to the stages throughout development. However, this section could be enhanced by adding an image of the normal eye structure and development – this acts as a reference point for your page viewers, allowing for a clear visual comparison between the abnormalities and normal structure.

2. Abnormal Development: I like the overview provided at the beginning as it sets the scene for what points you will be covering in this section. Great job. All sections are quite good, just perhaps include more images to further enhance your page.

a. Abnormal lens development: I liked how you first described the function of the gene in development and then stated any abnormalities that arise when the gene is not expressed or mutated. I liked how you included an image for the crystalline genes; just make sure to refer to the image in text (e.g. see fig. 1. or see accompanying image).

b. Abnormal corneal development: Similar to the abnormal lens section, there is a good explanation provided for each gene involved. Just some improvements: make sure to reference all information; e.g. No reference provided for “The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of....”. The accompanying image has been referenced correctly and described, good work!

c. Abnormal retinal development: Once again, a great scope of research and information and suitable image. I liked how you described the impact of each mutation explicitly such as in Albinism “ganglion cells of retina decreased by 25%”. This really helps the reader to understand the extent of the abnormalities from certain gene mutations.

3. Ocular manifestations: the opening sentence is slightly vague. Could you please state which two separate sections that you are referring to? The section that follows could be better organised. It seems to jump from genetic issues to a research timeline then to future research on that disease to another example of a genetic mutation which produces abnormalities. I would suggest putting the research timeline shortly after the introduction and integrating research history not just on LCA but other abnormalities as well. However, the content for all these sections is well referenced and interesting to read. The balance between text and images between LCA and anopthalmia/micropthalmia sections is good and are both really interesting to read! I liked how you provided some epidemiological data and clinical manifestations in depth accompanied by suitable images. However, the environmental abnormalities section could use with more dot-point styles and images to enhance the presentation and aid in your descriptions.

In regards to peer teaching (outcome 5), this page was an absolute joy to read and all technical language was explained in the glossary. Just make sure to pay attention to those minor improvements. Good job!"

====Hearing====

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

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

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

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

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

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

===Lab 9 Assessment===

====Embryonic Blood Flow and Oxygen and the Developing Pancreas====

''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.''

A study by Shah et al.<ref name="PMID21050843"><pubmed>21050843</pubmed></ref> sought to investigate whether enhanced blood flow and oxygen in a developing mouse pancreas correlates with changes in differentiation during embryonic pancreatic development. This investigation was prompted because "there is a fundamental lack of understanding of how organs in early mammalian embryos are able to form despite receiving little or no blood flow" according to Shah et al.

The methods involved injecting fluorescein-conjugated tomato lectin (a vascular tracer) into the hearts of developing mouse embryos ''in utero'' at different stages of development, guided by ultrasound backscatter microscopy. The vascular tracer was left to circulate for 10 minutes and then the mice embryos were harvested for analysis of blood flow and oxygenation. One key finding discovered through immunohistochemistry was that the developing pancreas had dense vascularity, though numerous vessels early in gestation were non-perfused. Vessels that were not perfused with blood did not induce differentiation of adjacent pancreatic epithelium. In contrast, vessels perfused with blood were surrounded by glucagon-positive and insulin-positive cells; these are indications of pancreatic cell differentiation. However, ''in vitro'' it was found that the hypoxic embryonic pancreas shows proliferation but not differentiation. Interestingly, the endocrine areas tended to be areas with flow and higher oxygenation compared to the exocrine areas of the pancreas. Moreover, later embryonic stages when global pancreatic perfusion occurred correlated with a rapid increase in exocrine differentiation. Overall, Shah et al. concluded that vascular flow with oxygenated blood, as opposed to just vascular endothelium alone, may provide specific signals for pancreatic differentiation in the early embryo.

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

Through the interaction between the neural crest and the ectoderm, 10 teeth buds form in the the embryo on in the early embryo<ref>Universities of Fribourg, Lausanne and Bern. (2012). ''Development of the Teeth''. Retrieved from http://www.embryology.ch/anglais/sdigestive/gesicht05.html</ref>. Each tooth bud has an outer area of ectodermal orgign (the enamel organ) with an inner area of dental pulp made up of solidified mesenchyme of neuroectodermal origin. The neuroectodermal mesenchyme also forms the dental follicle from which the periodontium and cement of the tooth root arise.

* '''Ectoderm''' of the oral cavity produces:
** Ameloblasts which produce the teeth enamel in the direction of the tooth pulp.
* Surrounding '''mesoderm''' (mesenchyme) in conjunction with '''neural crest''' produces:
** Odontoblasts excrete predentin below the ameloblast layer; dentin then arises through calcium salt deposition in the predentin.
** Cementoblasts in the root of the tooth produce cement.

'''References'''
<references/>

==Lab Attendance==
Lab 1 --[[User:Z3333038|Z3333038]] 11:49, 25 July 2012 (EST)

Lab 2 --[[User:Z3333038|Z3333038]] 10:05, 1 August 2012 (EST)

Lab 3 --[[User:Z3333038|Z3333038]] 10:01, 8 August 2012 (EST)

Lab 4 --[[User:Z3333038|Z3333038]] 10:00, 15 August 2012 (EST)

Lab 5 --[[User:Z3333038|Z3333038]] 09:59, 22 August 2012 (EST)

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2012 Group Project 4

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Z3333038: /* Clinical Features */

[[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

2012-10-02T23:55:37Z

Z3333038: /* Clinical Features */

[[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

2012-10-02T09:28:05Z

Z3333038: /* Congenital Abnormalities */

[[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 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.

'''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}}

User:Z3333038

2012-10-02T09:13:54Z

Z3333038: /* Developing Teeth */

==Individual Assessments==

===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 History of In Vitro Fertilisation====
In vitro fertilisation (IVF) refers to the process of artificial fertilisation conducted ex vivo. The IVF technique was first described for non-human use. The earliest known research conducted was by Walter Heape from Cambridge University in the 1890s who reported the first known case of embryo transplantation in rabbits. In 1959, Dr. Min Chueh Chang published his work in Nature describing the first successful mammalian live birth (rabbits) after IVF therapy.

Eventually, the use of IVF for humans became a possibility and then a reality: in 1978, the first successful birth from IVF occurred in England. The success of this IVF birth is credited to Patrick Steptoe and Robert Edwards. In 2010, Edwards was awarded the [http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/ Nobel Prize in Medicine] for the development of human IVF therapy. Because of IVF, many couples have been given a chance to conceive. However, the [http://www.ivf-worldwide.com/ivf-history.html/ history of IVF] is still in the making with constant improvements in the technology being developed and applied.

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

====Research in Fertilisation====

In order for fusion between mammalian gametes to occur, a spermatozoon must first pass through the external layers surrounding the oocyte: the cumulus oophorus and the zona pellucida (ZP). It is believe that the acromosome reaction (AR) of the spermatozoa starts upon contact with the zona pellucida. Consequently, the cumulus cell layer is typically removed in studies of mouse sperm-oocyte interactions in order to facilitate fertilisation. The recent experiments of Jin et al. <ref name="PMID21383182"><pubmed>21383182</pubmed></ref> sought to answer the question: "Where does the fertilising mouse spermatozoon begin the AR - in the cumulus [of the oocyte] or the zona pellucida?" Jin et al. <ref name="PMID21383182"/> utilised fluorescence microscopy and transgenic mouse spermatozoa to conduct their investigation. Additionally, Jin et al. <ref name="PMID21383182"/> used cumulus-free oocytes and cumulus-enclosed oocytes to study the role of the cumulus cells in fertilisation.

From the experiment, Jin et al. <ref name="PMID21383182"/> found that most fertilising spermatozoa begin the AR before their first contact with the ZP. The significance of this finding was that the spermatozoa with intact acromosomes at the ZP seldom had the ability to penetrate through <ref name="PMID21383182"/>. In contrast, spermatozoa which had already began the AR could easily penetrate the ZP. In regards to the role of the cumulus cells, it was found that cumulus-enclosed oocytes had a higher incidence of fertilisation compared to cumulus-free oocytes <ref name="PMID21383182"/>. Moreover, cumulus-free oocytes had an increased incidence of in vitro fertilisation when incubated with other cumulus-enclosed cells; this finding suggests that cumulus cells harbour an important role in fertilisation <ref name="PMID21383182"/>. However, it is notable that when cumulus-free oocytes were incubated in a cumulus-conditioned medium, no increase in fertilisation rate was noted<ref name="PMID21383182"/>. Overall, two conclusions were made: firstly, that the AR is required by the spermatozoa prior to meeting the ZP for effective fertilisation<ref name="PMID21383182"/>. Secondly, the cumulus oophorus confers benefit in increasing the chance of fertilisation<ref name="PMID21383182"/>.

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 16:58, 11 September 2012 (EST) Question 1 is answered well and linked to appropriate resources. Question 2 is also quite a complete answer to what I requested. The formatting of your description could have been better organised, while it is correct to cite the paper when referring to the findings, this is a little overboard with 9 times within 2 paragraphs. If you had organised the information differently this could have been reduced to 1-2 citations within the text. Alternatively the findings could have been provided as a bullet or numbered list. '''10/10'''

===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.''
====Patterns of ZPC Deposition in Porcine Oocyte-Cumulus Complexes====
[[File:Patterns_of_ZPC_Deposition_in_Porcine_Oocytes.jpg‎]]

Immunofluorescence Detection for ZPC and Ubiquitin in a Porcine Oocyte <ref name="PMID21383844"><pubmed>21383844</pubmed></ref>

'''References'''
<references/>

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

Trophinin is a membrane protein expressed in chorionic villi trophoblasts and in the maternal endometrium. In the early stages of pregnancy, trophinin is strongly expressed along with tastin and bystin, which form a complex; this complex mediates apical cell adhesion between the trophoblasts and the endometrial epithelial cells<ref name="PMID14633596"><pubmed>14633596</pubmed></ref>. The time frame in which trophinin is expressed on the apical aspect of the endometrial cells coincides with the "implantation window"<ref name="PMID14633596"/>; the period in which successful implantation is possible. Trophonin-trophonin adhesion during implantation occurs via signal transduction with bystin and tastin<ref name="PMID22201876"><pubmed>22201876</pubmed></ref>. As a consequence of trophinin-trophinin adhesion, trophectoderm cells become activated for implantation<ref name="PMID22201876"/>. Moreover, there have been reports that endometrial epithelial cells undergo apoptosis upon blastocyst adhesion; human trophoectoderm cells express the Fas ligand which interacts with Fas expressed on the endometrium<ref name="PMID22201876"/>. However, other studies have shown that trophinin-mediated cell adhesion can induce endometrial cell apoptosis through mechanisms other than the Fas/FasL cascade<ref name="PMID22201876"/>.

In regards to ectopic pregnancies located within the fallopian tube, research has shown that trophinin is strongly expressed by both the embryonic trophoblasts and maternal fallopian tube epithelium, induced by human chorionic gonadotrophin (hCG)<ref name="PMID14633596"/>. These findings highlight the function of trophonin in facilitating implantation in conjunction with its role in the pathogenesis of ectopic pregnancies.

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 17:04, 11 September 2012 (EST) Question 1 image has been correctly uploaded and contains all the requested information in the summary box. Question 2 is a good description of this recent paper on trophinin and Implantation. '''10/10'''

===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.''
====Gestational Age versus Post-Fertilisation Age====

Gestation is the period of time between conception and birth (Kaneshiro, 2011; Vishton, 2011). Gestational age is the developmental age of the conceptus based on the presumed first day of the last normal menstrual period to the current date, measured in weeks (Kaneshiro, 2011; Vishton, 2011). In contrast, post-fertilisation age refers to the age of the conceptus expressed in elapsed time since fertilisation (Vishton, 2011). Gestational age is approximately two weeks greater than post-fertilization age (Kaneshiro, 2011; Vishton, 2011). Gestational age is used in human development because its start date can be determined by asking the mother when was the presumed first day of the last normal menstrual period (Kaneshiro, 2011; Vishton, 2011). In contrast, the moment of fertilization must be inferred (Vishton, 2011).

'''References'''

Kaneshiro, N. K. (2011). ''Gestational age''. Retrieved from http://www.umm.edu/ency/article/002367.htm

Vishton, P. M. (2011). ''Embryo Foetus Development Stages''. Retrieved from http://www.livestrong.com/article/92683-embryo-fetus-development-stages/

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

====Tissues Derived From Somites====

'''1. Bone (Sclerotome)'''

Bone tissue consists of cells separated by an extracellular matrix with organic and inorganic components (Marieb, Wilhem & Mallatt, 2010). The organic components of bone consists of cells, collagen fibres and ground substance. The cells include osteoprogenitor cells which give rise to osteoblasts: the producers of new bone matrix (osteoid). Mature osteoblasts, called osteocytes, are trapped in lacunae where they maintain the mature bone; osteocytes may revert to osteoblasts in the incidence of a fracture. Osteoclasts are multinucleated cells with ruffled plasma membrane borders and are involved in bone resorption. Bone resorption is important for bone remodelling to improve tensile strength as well as remodel the newly deposited woven bone into mature bone after a fracture. There are two types of mature (lamellar) bone: compact bone and spongy bone (Marieb et al., 2010). The compact bone occurs towards the periphery and is arranged in Haversian systems: lamellae concentrically arranged around a central Haversian canal containing blood vessels, nerves and osteocytes (Marieb et al., 2010). The different Haversian systems communicate with each other, the periosteum and endosteum through the Volkmann's canals. In contrast, spongy bone in the mature adult appears towards the centre of the diaphysis and metaphysis and is arranged in bony shelves (trabeculae) (Marieb et al., 2010). The gross porous arrangement of spongy bone is important for housing the bone marrow (Marieb et al., 2010)

'''2. The Skin (Dermotome)'''

a. ''Dermis'': The dermis is made up of two main regions: (1) the superficial papillary layer and (2) the deeper reticular layer (Marieb et al., 2010). The superficial papillary layer makes up 20% of the dermis and is areolar connective tissue consisting of collagen and elastic fibres; it includes the dermal papillae which extend into the overlying epidermis to strengthen the dermal-epidermal junction and increase surface area for nutrient, gas and waste exchange with the avascular epidermis (Marieb et al., 2010). The reticular layer is composed of dense irregular connective tissue with thick bundles of collagen and elastic fibres arranged in different planes (Marieb et al., 2010). Other cells interspersed among the connective tissue of the dermis include fibroblasts, macrophages, mast cells and other white blood cells including lymphocytes(Marieb et al., 2010). The dermis is highly vascular and supplied with nerve fibres (Marieb et al., 2010). There are two vascular plexuses; the deep dermal plexus and the subpapillary plexus (Marieb et al., 2010). These vessels serve not only for nutrient supply to the dermis and epidermis, but for temperature regulation as well (Marieb et al., 2010).

b. ''Hypodermis'': The subcutaneous layer, or fatty hypodermis, consists of areolar and adipose connective tissue(Marieb et al., 2010). The cellular components include adipocytes as well as white blood cells (Marieb et al., 2010). The hypodermis serves to store fat and anchor the skin to underlying structure in a manner that the skin can slide over structures(Marieb et al., 2010). Additionally, the adipose in the hypodermis serves an insulator.

'''3. Skeletal Muscle (Myotome)'''
Skeletal muscle fibres come together to form a larger skeletal muscle surrounded by different levels of connective tissue "coats": the epimysium surrounds the whole skeletal muscle, the perimysium covers each fascicle and the loose CT endomysium separates each skeletal muscle fibre (Marieb et al., 2010). The skeletal muscle fibres are long cylindrical cells with a diameter between 10-100um (Marieb et al., 2010) . These muscle fbres are formed by the fusion of embryonic cells and hence contain many nuclei which are located at the periphery of each fibre beneath the sarcolemma, the skeletal muscle cell membrane (Marieb et al., 2010). These muscle fibres appear striated because of the internal organelles of the muscle fibres: myofibrils, the contractile organelles of muscle tissue (Marieb et al., 2010).

'''References'''

Marieb, E. N., Wilhelm, P. B., Mallatt, J. (2010). ''Human Anatomy'' (6th ed.). San Francisco, CA: Pearson Education, Inc.

--[[User:Z8600021|Mark Hill]] 17:10, 11 September 2012 (EST) Question 1 Clearly identified and cited the difference between "gestational age" and "post-fertilisation age". Question 2 you have also identified histological descriptions at least 3 different types of tissues formed from somites. For both questions you could have formatted the references and the reference list by using the <nowiki><ref></ref></nowiki> tags and simply inserted any text that you wanted in your list between the tags. '''10/10'''

===Lab 4 Assessment===

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

*'''Amniocentesis''' <ref>Moore, K. L., Persaud, T. V. N. & Torchia, M. G. (2013). ''The Developing Human'' (9th ed.). Philadelphia, PA: Elsevier Saunders. </ref>: Amniocentesis refers to sampling of the amniotic fluid by inserting a needle through the mother's anterior abdominal and uterine walls into the amniotic cavity by piercing the chorion and amnion. This technique is performed at 15 and 18 weeks gestation. Amniocentesis is often used to detect genetic disorders as it allows for chromosome analysis. One abnormality which can be detected is trisomy 21 (Down's Syndrome)[1]. Additionally, amniocentesis can be utilised for alpha-fetoprotein assays to detect neural tube defects like spina bifida [1].

*'''Chorionic Villus Sampling''' [1]: Biopsies of trophoblastic tissue are obtained by inserting a needle through the mother's abdominal wall and uterine walls to the uterine cavity. Sampling can also be performed through the cervix with a polyethylene catheter, guided by real-time ultrasonography. CVS can be performed sooner than amniocentesis at 10 and 12 weeks of gestation. However, the rate of miscarriage from CVS is higher than amniocentesis. Like amniocentesis, CVS can be used to detect chromosomal abnormalities like trisomy 21 as well as trisomy 18. Additionally, Tay-Sachs disease can be detected with CVS [1].

====The Therapeutic Use of Cord Stem Cells====
''2. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.''

Fu et al. (2006) sought to isolate human umbilical cord mesenchymal stem cells (HUCMSCs) and transform them into dopaminergic neurons in vitro <ref name="PMID16099997"><pubmed>16099997</pubmed></ref>. The experiment was carried out in the interest of finding a potential cure for Parkinson's disease from HUCMSCs [2]. The procedure involved isolating human mesenchymal stem cells from Wharton's jelly of the umbilical cord and culturing the HUCMSCs in a neuronal conditioned medium (NCM) [2]. The differentiation of the HUCMSCs into dopaminergic neurons was induced through stepwise culturing with the NCM, sonic hedgehog and FGF-8 [2]. The successfully transformed HUCMSCs into dopaminergic neurons were selected by positive immunohistochemistry staining for tyrosine hydroxylase (TH), the rate-limiting catecholaminergic synthesizing enzyme, and dopamine secretion [2]. These neurons were then transplanted into the striatum of rats with induced Parkinson's disease by unilateral striatal lesioning with neurotoxin (6-hydroxydopamine hydrogen chloride)[2]. The effects of stem cell transplantation were examined in the Parkinsonian animals by quantification of rotations in the mice in response to amphetamine at 0, 1, 2, 3 and 4 months [2].

Despite a success rate of 12.7% of transformed HUCMSCs, the study found that the original number of HUCMSCs doubled after 3 days of culture [2]. Additionally, the transformed HUCMSCs were still viable in the rats 4 months post-transplantation without the need for immunosuppression [2]. These findings highlight HUCMSCs as a potentially safe source of organs due to their viability post-surgery and the lack of a negative host response to the newly transplanted tissues. Additionally, positive TH staining showed migration of the transformed HUCMSCs rostrally and caudally from the location of implantation [2]. Hence, the transformed HUMSCs were able to integrate properly into the patient (Parkinsonian mouse), putting forth their suitability as a tissue source for transplantation.

The clinical effects of the HUCMSCs on the Parkinsonian mice were assessed by comparing test subjects to two control groups. The first control group consisted of normal, non-Parkinsonian mice with a low score of rotation in response to amphetamine. The second control group contained Parkinsonian mice which received no treatment and had a high rotation score [2]. It was found that the second control group showed no improvement in rotation score and deteriorated further over time. Similarly, mice treated with non-transformed HUCMSCs did not have observable improvements and had a similar deteriorating rotation score to the untreated Parkinsonian animals [2]. This finding highlights that untransformed HUCMSCs confer no clinical benefit in the setting of simulated Parkinson's disease [2]. The Parkinsonian mice treated with transformed HUCMSCs at first had no observable improvement but over time showed significantly improved rotational scores relative to the Parkinsonian control group [2]. However, the transformed HUCMSCs group did not show improvement to the extent of returning to a normal level (non-Parkinsonian rat). These findings suggest that HUCMSCs could be a potential stem cell source for transplantation, however, the procedures for HUMSCs transformation and transplantation must first be reviewed [2]. Fu et al. (2006) suggested that, the number of dopaminergic neurons of implanted cells may have been relatively inadequate to alleviate the Parkinsonism symptoms in the affected rats. Additionally, the transplanted cells may take time to integrate into the host brain: only two rats in the transformed HUCMSCs group survived for at least 8 months, with amphetamine-induced rotation behavior remaining similar to that 4 months after transplantation. Hence, in order to properly assess HUCMSCs to treat Parkinson's disease, the long-term effects of transplantation must be studied [2].

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 17:18, 11 September 2012 (EST) Question 1 well answered in terms of technique and specific abnormalities. Question 2 human umbilical cord mesenchymal stem cells in Wharton's jelly have been used in several studies as potential sources of therapeutic cells. Perhaps a more recent paper next time. '''10/10'''

===Lab 7 Assessment===

====Muscle Satellite Cells====

''1. (a) Provide a one sentence definition of a muscle satellite cell''

Satellite cells are quiescent cells located beneath the basal lamina of each myofibre and function as myogenic precursors (stem cells) for postnatal muscle growth and repair <ref name="PMID16051152"><pubmed>16051152</pubmed></ref>.

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

Muscle satellite cells are at rest (G0) when skeletal muscle is not active<ref name="PMID22649641"><pubmed>22649641</pubmed></ref>. Activation can occur in the settings of physical activity and mechanical trauma <ref name="PMID12892408"/>. When satellite cells are activated, they proliferate and are converted to myoblasts which further differentiate and fuse with existing muscle fibres or form new fibres <ref name="PMID12892408"><pubmed>12892408</pubmed></ref>. The myonuclei accumulated in the tissue are of key importance for myogenesis: they aid in increasing protein synthesis and enable muscle growth (hypertrophy and hyperplasia) and regeneration<ref name="PMID16051152"/>. Without satellite cells, mature muscle fibres are unable to undergo regeneration <ref name="PMID16051152"/>. There is much speculation as to the exact mechanisms and factors which activate muscle satellite cells. It is proposed that strenuous exercise, mechanical muscle injury or myodegenerative disease result in the inflammatory response which recruits neutrophils and macrophages to the area of damage; the inflammatory mediators released in conjunction with growth factors secreted by the myofibres promote myosatellite activation <ref name="PMID12892408"/>. One proposed "triggering agent" is the production of sphingosine-1-phosphate from the inner part of the plasma membrane leading to satellite cell entry into the cell cycle <ref name="PMID17996437"><pubmed>17996437</pubmed></ref>. Additionally, mechanical stretch to the muscle fibre has been shown to trigger intracellular signals, such as nitric oxide synthesis which results in hepatocyte growth factor (HGF) release <ref name="PMID17996437"/>. Nitric oxide also induces follistatin, a fusigenic secreted molecule, which is an antagonist to myostatin. Myostatin is expressed by quiescent satellite cells and exerts a negative effect on satellite cell activation <ref name="PMID17996437"/>. IGF-IEa and MGF have also been implicated in satellite cell activation: Hill et al. (2003) demonstrated that these mediators are produced by active muscle in rodents and appear to be positive regulators of muscle hypertrophy<ref name="PMID12892408"><pubmed>12892408</pubmed></ref>. However, whilst MGF is acutely induced and is said to precede satellite cell activation, IGF-IEa has a delayed effect involved in the later phase of regeneration<ref name="PMID12892408"/>. Interestingly, in dystrophic muscles MGF is not produced, suggesting the importance of effective muscle repair to avoid the pathogenesis of muscular dystrophy syndromes <ref name="PMID12892408"/>.

Once activated, the satellite cells migrate out of the basal lamina and enter the cell cycle with coexpression of Pax7 and MyoD <ref name="PMID17996437"/>. This process occurs in conjunction with the Notch signaling pathway<ref name="PMID22493066"><pubmed>22493066</pubmed></ref>. The skeletal myoblasts that are produced divide, express myogenin and downregulate Pax7 then fuse to form myofibres<ref name="PMID17996437"/>.

====The Effects of Motor Nerve Damage on Skeletal Muscle====

''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?''

Chronic spinal cord injury (SCI) affects muscles below the level of the lesion. In terms of fibre type, one review <ref name="PMID19705475"><pubmed>19705475</pubmed></ref>describes the progressive change in fibre type toward faster phenotypes. The fibre phenotype is classified according to its myosin heavy chain (MHC) molecule which is an actin-based motor protein associated with muscle fibre contraction<ref name="PMID19705475"/>. These three MHC isoforms are MHC I, MHC IIa, and MHC IIx <ref name="PMID19705475"/>. In SCI there is a reduction of type I fibres (slow) and upregulation of type IIA and IIX fibres (fast)<ref name="PMID19705475"/>. The metabolism of the fast fibres is characterised by a predominantly anaerobic metabolism with fewer mitochondria, unlike type I fibres which undergo aerobic metabolism <ref name="PMID19705475"/>. This is in part due to a reduction in absolute activities of the muscle metabolic enzymes in SCI, favouring the fast glycolytic/oxidative type which fatigue more easily <ref name="PMID19705475"/>.

In terms of fibre size, a study by Castro et al. (1998) <ref name="PMID9887150"><pubmed>9887150</pubmed></ref> found that all fibre types underwent significant atrophy and decreased in size from the 6th to 24th week after injury<ref name="PMID9887150"/>. Moreover, average fibre cross-sectional area decreased by 22% by the 6th week post-injury <ref name="PMID9887150"/>. The changes were accompanied by either complete paralysis or loss of force with increased susceptibility to fatigue depending on the extent of injury <ref name="PMID9887150"/>. Note that whilst type II fibre atrophy is seen during the first months after complete SCI, type I fibres undergo atrophy in the later stages <ref name="PMID19705475"><pubmed>19705475</pubmed></ref>.

Interestingly, the level of the motor neuron lesion can affect the outcome of the muscle atrophy: a study by Stilwill and Sagha <ref name="PMID66912"><pubmed>66912</pubmed></ref>found that lower motor neuron lesions led to muscle fibre grouped atrophy and fibre-type grouping, whereas upper motor neuron lesions led to preferential atrophy of type II fibers with fibre-type grouping.

'''References'''
<references/>

===Lab 8 Assessment===
1. Each student should now look at each of the other Group projects in the class.

2. Next prepare a critical assessment (should include both positive and negative issues) of each project using the project assessment criteria.

3. This assessment should be pasted without signature on the top of the specific project's discussion page. (minimum length 3-5 paragraphs/project)

4. This critical assessment should also be pasted on your own student page. Each student should therefore have 5 separate reports pasted on their own page for this assessment item. Length, quality and accuracy of your reports will be part of the overall mark for this assessment (there will be a greater loading on this than simple question assessments).

====Vision====
In regards to the information presented (outcomes 1 and 9), as the project is still in progress it is understandable that some areas are incomplete. There is so far good, concise information on the structure of the development of the eye and the structures involved in vision. It would be useful to include information on the genetic factors involved in vision development as well as have a section explaining the processes involved with vision. Also, for the Current Research section (outcome 5), it would be better to explain the aims and findings of the research papers cited rather than just referencing the papers and images without describing their significance to research progress. In terms of peer teaching (outcome 4), the page contains a good balance between technical terms and simple language for understanding on the development of structures for vision; additionally, the inclusion Glossary helps to clarify any technical terms.

The most striking part of the layout (outcome 2) is the use of images to demonstrate the development of structures involved in vision. This is great because it makes the page interesting and provides a visual understanding on the development of the eye. However, at times the images could be better placed: for example, in the introduction the pictures appear stacked on top of one another. Additionally, the images in the introduction show similar structures, so perhaps select only one to better aid the flow and appearance of the page. Throughout the page, the images utilised could be provided with more description and linked to the text in order to improve flow and enhance written explanation. Perhaps some information, such as the timeline, could be sorted into a table to improve the layout.

In regards to outcome 3, some of the information provided (e.g. in the section on Development) is not referenced. Additionally, some of the references in the Reference list need to be formatted correctly with author, date, title of the page, publisher (if required) and any other necessary information. It would be useful to follow the style of the automatic default referencing.
Hope the feedback helps and all the best with your project!

====Somatosensory====
The introduction is good in that there is a description of the role of somatosensory functions as well as an overview of its development. To improve further, perhaps avoid trailing off in the final sentence and perhaps put something that concludes your introduction.

In regards to the information presented and layout (outcomes 1, 2, 4 and 9), the history of discoveries is very brief and requires more research. Additionally, it would be useful to set up a timeline to add interest. The section on the central somatosensory differentiation appeared very well researched with a very interesting picture to accompany the text – good work. The section on Touch would better be placed in a table and have accompanying images to avoid getting too ‘wordy’. Also, this section does not have any consistent referencing in the bulk of the content – please cite where you find your information. The section on pain is well researched and has a strong content, however, to enhance this section I would suggest using dot points to describe the different fibres and add a relevant image. Similarly, the hot/cold and pressure sections were great in terms of content but could use with some dot points and visual explanation to make the page more interesting. Just a note on pressure – avoid getting repetitive; the page had already defined the Ruffini’s endings/corpuscles etc in the section of Touch. Additionally, the 2 urls at the bottom of this section are distracting, make sure to incorporate these in your reference list of add them to an ‘External Links’ section. Your Current Research section requires some proof reading and additional articles to make it more comprehensive. However, you have referenced the image well and referred to it in the accompanying text.

In terms of referencing, I noticed some areas where the in-text references were not correctly formatted and were in the (Author, date) style. Perhaps have a look at the referencing tutorial on the Embryology ‘Students’ page to get an understanding of the codes required for citations. For peer teaching (outcome 4), make sure that you define all technical terms – your Glossary only has 2 definitions provided. Other than this, the content overall is interesting to read just make sure you are striking a balance between images and text. Hope it helps and all the best!

====Taste====

In regards to the information presented (outcomes 1 and 9), the timeline for the development is good and written with clarity. However, I noticed the section on structure only referred to the adult state rather than focusing on the embryonic origin of each structure (ectoderm, endoderm and mesoderm). I would suggest that you elaborate on the developmental stages introduced in the timeline in order to build on the information you have already provided. This is important in regards to outcome 6 so that you can relate your research to embryology – the development of taste should be your focus. The history timeline was great to read as it was very concise and clear.

The page shows a good level of peer teaching with clear language and a good balance between images and text (outcome 4) with technical terms explained in the glossary. An improvement could be to make a link between any technical language and the glossary to avoid scrolling up and down to the page. Your Current Research section (outcome 5) was very interesting to read and showed you went beyond the scope of basic research on taste – good work!

In terms of layout (outcome 2), whilst the images are interesting and relevant to the text, some are not appropriately referenced nor described; make sure to reference appropriately and at least write one or two sentences to make the images relevant to the reader. Additionally, the introduction should not be under another subheading (Gustatory system) as it creates some confusion; I would suggest making the introduction its own heading in order to make the page flow. Similarly, the history timeline would best be placed towards the beginning of the page, under the introduction.

I noticed some areas (such as the section on Structure) were not appropriately or consistently referenced. Make sure to include a citation anytime you introduce a researched idea or information to avoid being accused of plagiarism. I noticed the history timeline had good consistent referencing; however the numbers just need to be formatted so they come under the reference list. If you click on the Tutorial: References page linked from the student page, it tells you how to do this. Hope the feedback helps and all the best for your project!

====Abnormal Vision====
"The introduction is good in the manner that it provides some brief background information regarding the normal development of the eye and abnormalities. Additionally, I liked how the introduction described the aims of the page because it sets up a structure for the reader to follow. Just make sure to proof read this section: “The development of the eye is very sensitive and REQUIRES accurate...”

In regards to the information presented and layout (outcomes 1, 2, 4 and 9):

1. Normal Eye Development: This section appears very well researched. I like how you referred to the stages throughout development. However, this section could be enhanced by adding an image of the normal eye structure and development – this acts as a reference point for your page viewers, allowing for a clear visual comparison between the abnormalities and normal structure.

2. Abnormal Development: I like the overview provided at the beginning as it sets the scene for what points you will be covering in this section. Great job. All sections are quite good, just perhaps include more images to further enhance your page.

a. Abnormal lens development: I liked how you first described the function of the gene in development and then stated any abnormalities that arise when the gene is not expressed or mutated. I liked how you included an image for the crystalline genes; just make sure to refer to the image in text (e.g. see fig. 1. or see accompanying image).

b. Abnormal corneal development: Similar to the abnormal lens section, there is a good explanation provided for each gene involved. Just some improvements: make sure to reference all information; e.g. No reference provided for “The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of....”. The accompanying image has been referenced correctly and described, good work!

c. Abnormal retinal development: Once again, a great scope of research and information and suitable image. I liked how you described the impact of each mutation explicitly such as in Albinism “ganglion cells of retina decreased by 25%”. This really helps the reader to understand the extent of the abnormalities from certain gene mutations.

3. Ocular manifestations: the opening sentence is slightly vague. Could you please state which two separate sections that you are referring to? The section that follows could be better organised. It seems to jump from genetic issues to a research timeline then to future research on that disease to another example of a genetic mutation which produces abnormalities. I would suggest putting the research timeline shortly after the introduction and integrating research history not just on LCA but other abnormalities as well. However, the content for all these sections is well referenced and interesting to read. The balance between text and images between LCA and anopthalmia/micropthalmia sections is good and are both really interesting to read! I liked how you provided some epidemiological data and clinical manifestations in depth accompanied by suitable images. However, the environmental abnormalities section could use with more dot-point styles and images to enhance the presentation and aid in your descriptions.

In regards to peer teaching (outcome 5), this page was an absolute joy to read and all technical language was explained in the glossary. Just make sure to pay attention to those minor improvements. Good job!"

====Hearing====

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

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

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

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

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

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

===Lab 9 Assessment===

====Embryonic Blood Flow and Oxygen and the Developing Pancreas====

''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.''

A study by Shah et al.<ref name="PMID21050843"><pubmed>21050843</pubmed></ref> sought to investigate whether enhanced blood flow and oxygen in a developing mouse pancreas correlates with changes in differentiation during embryonic pancreatic development. This investigation was prompted because "there is a fundamental lack of understanding of how organs in early mammalian embryos are able to form despite receiving little or no blood flow" according to Shah et al.

The methods involved injecting fluorescein-conjugated tomato lectin (a vascular tracer) into the hearts of developing mouse embryos ''in utero'' at different stages of development, guided by ultrasound backscatter microscopy. The vascular tracer was left to circulate for 10 minutes and then the mice embryos were harvested for analysis of blood flow and oxygenation. One key finding discovered through immunohistochemistry was that the developing pancreas had dense vascularity, though numerous vessels early in gestation were non-perfused. Vessels that were not perfused with blood did not induce differentiation of adjacent pancreatic epithelium. In contrast, vessels perfused with blood were surrounded by glucagon-positive and insulin-positive cells; these are indications of pancreatic cell differentiation. However, ''in vitro'' it was found that the hypoxic embryonic pancreas shows proliferation but not differentiation. Interestingly, the endocrine areas tended to be areas with flow and higher oxygenation compared to the exocrine areas of the pancreas. Moreover, later embryonic stages when global pancreatic perfusion occurred correlated with a rapid increase in exocrine differentiation. Overall, Shah et al. concluded that vascular flow with oxygenated blood, as opposed to just vascular endothelium alone, may provide specific signals for pancreatic differentiation in the early embryo.

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

Through the interaction between the neural crest and the ectoderm, 10 teeth buds form in the the embryo on in the early embryo<ref>Universities of Fribourg, Lausanne and Bern. (2012). ''Development of the Teeth''. Retrieved from http://www.embryology.ch/anglais/sdigestive/gesicht05.html</ref>. Each tooth bud has an outer area of ectodermal orgign (the enamel organ) with an inner area of dental pulp made up of solidified mesenchyme of neuroectodermal origin. The neuroectodermal mesenchyme also forms the dental follicle from which the periodontium and cement of the tooth root arise.

* '''Ectoderm''' of the oral cavity produces:
** Ameloblasts which produce the teeth enamel in the direction of the tooth pulp.
* Surrounding '''mesoderm''' (mesenchyme) in conjunction with '''neural crest''' produces:
** Odontoblasts excrete predentin below the ameloblast layer; dentin then arises through calcium salt deposition in the predentin.
** Cementoblasts in the root of the tooth produce cement.

'''References'''
<references/>

==Lab Attendance==
Lab 1 --[[User:Z3333038|Z3333038]] 11:49, 25 July 2012 (EST)

Lab 2 --[[User:Z3333038|Z3333038]] 10:05, 1 August 2012 (EST)

Lab 3 --[[User:Z3333038|Z3333038]] 10:01, 8 August 2012 (EST)

Lab 4 --[[User:Z3333038|Z3333038]] 10:00, 15 August 2012 (EST)

Lab 5 --[[User:Z3333038|Z3333038]] 09:59, 22 August 2012 (EST)

Lab 6 --[[User:Z3333038|Z3333038]] 10:10, 29 August 2012 (EST)

Lab 7 --[[User:Z3333038|Z3333038]] 10:09, 12 September 2012 (EST)

Lab 8 --[[User:Z3333038|Z3333038]] 10:00, 19 September 2012 (EST)

Lab 9 --[[User:Z3333038|Z3333038]] 10:03, 26 September 2012 (EST)

User:Z3333038

2012-10-02T09:13:15Z

Z3333038: /* Lab 9 Assessment */

==Individual Assessments==

===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 History of In Vitro Fertilisation====
In vitro fertilisation (IVF) refers to the process of artificial fertilisation conducted ex vivo. The IVF technique was first described for non-human use. The earliest known research conducted was by Walter Heape from Cambridge University in the 1890s who reported the first known case of embryo transplantation in rabbits. In 1959, Dr. Min Chueh Chang published his work in Nature describing the first successful mammalian live birth (rabbits) after IVF therapy.

Eventually, the use of IVF for humans became a possibility and then a reality: in 1978, the first successful birth from IVF occurred in England. The success of this IVF birth is credited to Patrick Steptoe and Robert Edwards. In 2010, Edwards was awarded the [http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/ Nobel Prize in Medicine] for the development of human IVF therapy. Because of IVF, many couples have been given a chance to conceive. However, the [http://www.ivf-worldwide.com/ivf-history.html/ history of IVF] is still in the making with constant improvements in the technology being developed and applied.

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

====Research in Fertilisation====

In order for fusion between mammalian gametes to occur, a spermatozoon must first pass through the external layers surrounding the oocyte: the cumulus oophorus and the zona pellucida (ZP). It is believe that the acromosome reaction (AR) of the spermatozoa starts upon contact with the zona pellucida. Consequently, the cumulus cell layer is typically removed in studies of mouse sperm-oocyte interactions in order to facilitate fertilisation. The recent experiments of Jin et al. <ref name="PMID21383182"><pubmed>21383182</pubmed></ref> sought to answer the question: "Where does the fertilising mouse spermatozoon begin the AR - in the cumulus [of the oocyte] or the zona pellucida?" Jin et al. <ref name="PMID21383182"/> utilised fluorescence microscopy and transgenic mouse spermatozoa to conduct their investigation. Additionally, Jin et al. <ref name="PMID21383182"/> used cumulus-free oocytes and cumulus-enclosed oocytes to study the role of the cumulus cells in fertilisation.

From the experiment, Jin et al. <ref name="PMID21383182"/> found that most fertilising spermatozoa begin the AR before their first contact with the ZP. The significance of this finding was that the spermatozoa with intact acromosomes at the ZP seldom had the ability to penetrate through <ref name="PMID21383182"/>. In contrast, spermatozoa which had already began the AR could easily penetrate the ZP. In regards to the role of the cumulus cells, it was found that cumulus-enclosed oocytes had a higher incidence of fertilisation compared to cumulus-free oocytes <ref name="PMID21383182"/>. Moreover, cumulus-free oocytes had an increased incidence of in vitro fertilisation when incubated with other cumulus-enclosed cells; this finding suggests that cumulus cells harbour an important role in fertilisation <ref name="PMID21383182"/>. However, it is notable that when cumulus-free oocytes were incubated in a cumulus-conditioned medium, no increase in fertilisation rate was noted<ref name="PMID21383182"/>. Overall, two conclusions were made: firstly, that the AR is required by the spermatozoa prior to meeting the ZP for effective fertilisation<ref name="PMID21383182"/>. Secondly, the cumulus oophorus confers benefit in increasing the chance of fertilisation<ref name="PMID21383182"/>.

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 16:58, 11 September 2012 (EST) Question 1 is answered well and linked to appropriate resources. Question 2 is also quite a complete answer to what I requested. The formatting of your description could have been better organised, while it is correct to cite the paper when referring to the findings, this is a little overboard with 9 times within 2 paragraphs. If you had organised the information differently this could have been reduced to 1-2 citations within the text. Alternatively the findings could have been provided as a bullet or numbered list. '''10/10'''

===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.''
====Patterns of ZPC Deposition in Porcine Oocyte-Cumulus Complexes====
[[File:Patterns_of_ZPC_Deposition_in_Porcine_Oocytes.jpg‎]]

Immunofluorescence Detection for ZPC and Ubiquitin in a Porcine Oocyte <ref name="PMID21383844"><pubmed>21383844</pubmed></ref>

'''References'''
<references/>

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

Trophinin is a membrane protein expressed in chorionic villi trophoblasts and in the maternal endometrium. In the early stages of pregnancy, trophinin is strongly expressed along with tastin and bystin, which form a complex; this complex mediates apical cell adhesion between the trophoblasts and the endometrial epithelial cells<ref name="PMID14633596"><pubmed>14633596</pubmed></ref>. The time frame in which trophinin is expressed on the apical aspect of the endometrial cells coincides with the "implantation window"<ref name="PMID14633596"/>; the period in which successful implantation is possible. Trophonin-trophonin adhesion during implantation occurs via signal transduction with bystin and tastin<ref name="PMID22201876"><pubmed>22201876</pubmed></ref>. As a consequence of trophinin-trophinin adhesion, trophectoderm cells become activated for implantation<ref name="PMID22201876"/>. Moreover, there have been reports that endometrial epithelial cells undergo apoptosis upon blastocyst adhesion; human trophoectoderm cells express the Fas ligand which interacts with Fas expressed on the endometrium<ref name="PMID22201876"/>. However, other studies have shown that trophinin-mediated cell adhesion can induce endometrial cell apoptosis through mechanisms other than the Fas/FasL cascade<ref name="PMID22201876"/>.

In regards to ectopic pregnancies located within the fallopian tube, research has shown that trophinin is strongly expressed by both the embryonic trophoblasts and maternal fallopian tube epithelium, induced by human chorionic gonadotrophin (hCG)<ref name="PMID14633596"/>. These findings highlight the function of trophonin in facilitating implantation in conjunction with its role in the pathogenesis of ectopic pregnancies.

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 17:04, 11 September 2012 (EST) Question 1 image has been correctly uploaded and contains all the requested information in the summary box. Question 2 is a good description of this recent paper on trophinin and Implantation. '''10/10'''

===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.''
====Gestational Age versus Post-Fertilisation Age====

Gestation is the period of time between conception and birth (Kaneshiro, 2011; Vishton, 2011). Gestational age is the developmental age of the conceptus based on the presumed first day of the last normal menstrual period to the current date, measured in weeks (Kaneshiro, 2011; Vishton, 2011). In contrast, post-fertilisation age refers to the age of the conceptus expressed in elapsed time since fertilisation (Vishton, 2011). Gestational age is approximately two weeks greater than post-fertilization age (Kaneshiro, 2011; Vishton, 2011). Gestational age is used in human development because its start date can be determined by asking the mother when was the presumed first day of the last normal menstrual period (Kaneshiro, 2011; Vishton, 2011). In contrast, the moment of fertilization must be inferred (Vishton, 2011).

'''References'''

Kaneshiro, N. K. (2011). ''Gestational age''. Retrieved from http://www.umm.edu/ency/article/002367.htm

Vishton, P. M. (2011). ''Embryo Foetus Development Stages''. Retrieved from http://www.livestrong.com/article/92683-embryo-fetus-development-stages/

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

====Tissues Derived From Somites====

'''1. Bone (Sclerotome)'''

Bone tissue consists of cells separated by an extracellular matrix with organic and inorganic components (Marieb, Wilhem & Mallatt, 2010). The organic components of bone consists of cells, collagen fibres and ground substance. The cells include osteoprogenitor cells which give rise to osteoblasts: the producers of new bone matrix (osteoid). Mature osteoblasts, called osteocytes, are trapped in lacunae where they maintain the mature bone; osteocytes may revert to osteoblasts in the incidence of a fracture. Osteoclasts are multinucleated cells with ruffled plasma membrane borders and are involved in bone resorption. Bone resorption is important for bone remodelling to improve tensile strength as well as remodel the newly deposited woven bone into mature bone after a fracture. There are two types of mature (lamellar) bone: compact bone and spongy bone (Marieb et al., 2010). The compact bone occurs towards the periphery and is arranged in Haversian systems: lamellae concentrically arranged around a central Haversian canal containing blood vessels, nerves and osteocytes (Marieb et al., 2010). The different Haversian systems communicate with each other, the periosteum and endosteum through the Volkmann's canals. In contrast, spongy bone in the mature adult appears towards the centre of the diaphysis and metaphysis and is arranged in bony shelves (trabeculae) (Marieb et al., 2010). The gross porous arrangement of spongy bone is important for housing the bone marrow (Marieb et al., 2010)

'''2. The Skin (Dermotome)'''

a. ''Dermis'': The dermis is made up of two main regions: (1) the superficial papillary layer and (2) the deeper reticular layer (Marieb et al., 2010). The superficial papillary layer makes up 20% of the dermis and is areolar connective tissue consisting of collagen and elastic fibres; it includes the dermal papillae which extend into the overlying epidermis to strengthen the dermal-epidermal junction and increase surface area for nutrient, gas and waste exchange with the avascular epidermis (Marieb et al., 2010). The reticular layer is composed of dense irregular connective tissue with thick bundles of collagen and elastic fibres arranged in different planes (Marieb et al., 2010). Other cells interspersed among the connective tissue of the dermis include fibroblasts, macrophages, mast cells and other white blood cells including lymphocytes(Marieb et al., 2010). The dermis is highly vascular and supplied with nerve fibres (Marieb et al., 2010). There are two vascular plexuses; the deep dermal plexus and the subpapillary plexus (Marieb et al., 2010). These vessels serve not only for nutrient supply to the dermis and epidermis, but for temperature regulation as well (Marieb et al., 2010).

b. ''Hypodermis'': The subcutaneous layer, or fatty hypodermis, consists of areolar and adipose connective tissue(Marieb et al., 2010). The cellular components include adipocytes as well as white blood cells (Marieb et al., 2010). The hypodermis serves to store fat and anchor the skin to underlying structure in a manner that the skin can slide over structures(Marieb et al., 2010). Additionally, the adipose in the hypodermis serves an insulator.

'''3. Skeletal Muscle (Myotome)'''
Skeletal muscle fibres come together to form a larger skeletal muscle surrounded by different levels of connective tissue "coats": the epimysium surrounds the whole skeletal muscle, the perimysium covers each fascicle and the loose CT endomysium separates each skeletal muscle fibre (Marieb et al., 2010). The skeletal muscle fibres are long cylindrical cells with a diameter between 10-100um (Marieb et al., 2010) . These muscle fbres are formed by the fusion of embryonic cells and hence contain many nuclei which are located at the periphery of each fibre beneath the sarcolemma, the skeletal muscle cell membrane (Marieb et al., 2010). These muscle fibres appear striated because of the internal organelles of the muscle fibres: myofibrils, the contractile organelles of muscle tissue (Marieb et al., 2010).

'''References'''

Marieb, E. N., Wilhelm, P. B., Mallatt, J. (2010). ''Human Anatomy'' (6th ed.). San Francisco, CA: Pearson Education, Inc.

--[[User:Z8600021|Mark Hill]] 17:10, 11 September 2012 (EST) Question 1 Clearly identified and cited the difference between "gestational age" and "post-fertilisation age". Question 2 you have also identified histological descriptions at least 3 different types of tissues formed from somites. For both questions you could have formatted the references and the reference list by using the <nowiki><ref></ref></nowiki> tags and simply inserted any text that you wanted in your list between the tags. '''10/10'''

===Lab 4 Assessment===

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

*'''Amniocentesis''' <ref>Moore, K. L., Persaud, T. V. N. & Torchia, M. G. (2013). ''The Developing Human'' (9th ed.). Philadelphia, PA: Elsevier Saunders. </ref>: Amniocentesis refers to sampling of the amniotic fluid by inserting a needle through the mother's anterior abdominal and uterine walls into the amniotic cavity by piercing the chorion and amnion. This technique is performed at 15 and 18 weeks gestation. Amniocentesis is often used to detect genetic disorders as it allows for chromosome analysis. One abnormality which can be detected is trisomy 21 (Down's Syndrome)[1]. Additionally, amniocentesis can be utilised for alpha-fetoprotein assays to detect neural tube defects like spina bifida [1].

*'''Chorionic Villus Sampling''' [1]: Biopsies of trophoblastic tissue are obtained by inserting a needle through the mother's abdominal wall and uterine walls to the uterine cavity. Sampling can also be performed through the cervix with a polyethylene catheter, guided by real-time ultrasonography. CVS can be performed sooner than amniocentesis at 10 and 12 weeks of gestation. However, the rate of miscarriage from CVS is higher than amniocentesis. Like amniocentesis, CVS can be used to detect chromosomal abnormalities like trisomy 21 as well as trisomy 18. Additionally, Tay-Sachs disease can be detected with CVS [1].

====The Therapeutic Use of Cord Stem Cells====
''2. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.''

Fu et al. (2006) sought to isolate human umbilical cord mesenchymal stem cells (HUCMSCs) and transform them into dopaminergic neurons in vitro <ref name="PMID16099997"><pubmed>16099997</pubmed></ref>. The experiment was carried out in the interest of finding a potential cure for Parkinson's disease from HUCMSCs [2]. The procedure involved isolating human mesenchymal stem cells from Wharton's jelly of the umbilical cord and culturing the HUCMSCs in a neuronal conditioned medium (NCM) [2]. The differentiation of the HUCMSCs into dopaminergic neurons was induced through stepwise culturing with the NCM, sonic hedgehog and FGF-8 [2]. The successfully transformed HUCMSCs into dopaminergic neurons were selected by positive immunohistochemistry staining for tyrosine hydroxylase (TH), the rate-limiting catecholaminergic synthesizing enzyme, and dopamine secretion [2]. These neurons were then transplanted into the striatum of rats with induced Parkinson's disease by unilateral striatal lesioning with neurotoxin (6-hydroxydopamine hydrogen chloride)[2]. The effects of stem cell transplantation were examined in the Parkinsonian animals by quantification of rotations in the mice in response to amphetamine at 0, 1, 2, 3 and 4 months [2].

Despite a success rate of 12.7% of transformed HUCMSCs, the study found that the original number of HUCMSCs doubled after 3 days of culture [2]. Additionally, the transformed HUCMSCs were still viable in the rats 4 months post-transplantation without the need for immunosuppression [2]. These findings highlight HUCMSCs as a potentially safe source of organs due to their viability post-surgery and the lack of a negative host response to the newly transplanted tissues. Additionally, positive TH staining showed migration of the transformed HUCMSCs rostrally and caudally from the location of implantation [2]. Hence, the transformed HUMSCs were able to integrate properly into the patient (Parkinsonian mouse), putting forth their suitability as a tissue source for transplantation.

The clinical effects of the HUCMSCs on the Parkinsonian mice were assessed by comparing test subjects to two control groups. The first control group consisted of normal, non-Parkinsonian mice with a low score of rotation in response to amphetamine. The second control group contained Parkinsonian mice which received no treatment and had a high rotation score [2]. It was found that the second control group showed no improvement in rotation score and deteriorated further over time. Similarly, mice treated with non-transformed HUCMSCs did not have observable improvements and had a similar deteriorating rotation score to the untreated Parkinsonian animals [2]. This finding highlights that untransformed HUCMSCs confer no clinical benefit in the setting of simulated Parkinson's disease [2]. The Parkinsonian mice treated with transformed HUCMSCs at first had no observable improvement but over time showed significantly improved rotational scores relative to the Parkinsonian control group [2]. However, the transformed HUCMSCs group did not show improvement to the extent of returning to a normal level (non-Parkinsonian rat). These findings suggest that HUCMSCs could be a potential stem cell source for transplantation, however, the procedures for HUMSCs transformation and transplantation must first be reviewed [2]. Fu et al. (2006) suggested that, the number of dopaminergic neurons of implanted cells may have been relatively inadequate to alleviate the Parkinsonism symptoms in the affected rats. Additionally, the transplanted cells may take time to integrate into the host brain: only two rats in the transformed HUCMSCs group survived for at least 8 months, with amphetamine-induced rotation behavior remaining similar to that 4 months after transplantation. Hence, in order to properly assess HUCMSCs to treat Parkinson's disease, the long-term effects of transplantation must be studied [2].

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 17:18, 11 September 2012 (EST) Question 1 well answered in terms of technique and specific abnormalities. Question 2 human umbilical cord mesenchymal stem cells in Wharton's jelly have been used in several studies as potential sources of therapeutic cells. Perhaps a more recent paper next time. '''10/10'''

===Lab 7 Assessment===

====Muscle Satellite Cells====

''1. (a) Provide a one sentence definition of a muscle satellite cell''

Satellite cells are quiescent cells located beneath the basal lamina of each myofibre and function as myogenic precursors (stem cells) for postnatal muscle growth and repair <ref name="PMID16051152"><pubmed>16051152</pubmed></ref>.

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

Muscle satellite cells are at rest (G0) when skeletal muscle is not active<ref name="PMID22649641"><pubmed>22649641</pubmed></ref>. Activation can occur in the settings of physical activity and mechanical trauma <ref name="PMID12892408"/>. When satellite cells are activated, they proliferate and are converted to myoblasts which further differentiate and fuse with existing muscle fibres or form new fibres <ref name="PMID12892408"><pubmed>12892408</pubmed></ref>. The myonuclei accumulated in the tissue are of key importance for myogenesis: they aid in increasing protein synthesis and enable muscle growth (hypertrophy and hyperplasia) and regeneration<ref name="PMID16051152"/>. Without satellite cells, mature muscle fibres are unable to undergo regeneration <ref name="PMID16051152"/>. There is much speculation as to the exact mechanisms and factors which activate muscle satellite cells. It is proposed that strenuous exercise, mechanical muscle injury or myodegenerative disease result in the inflammatory response which recruits neutrophils and macrophages to the area of damage; the inflammatory mediators released in conjunction with growth factors secreted by the myofibres promote myosatellite activation <ref name="PMID12892408"/>. One proposed "triggering agent" is the production of sphingosine-1-phosphate from the inner part of the plasma membrane leading to satellite cell entry into the cell cycle <ref name="PMID17996437"><pubmed>17996437</pubmed></ref>. Additionally, mechanical stretch to the muscle fibre has been shown to trigger intracellular signals, such as nitric oxide synthesis which results in hepatocyte growth factor (HGF) release <ref name="PMID17996437"/>. Nitric oxide also induces follistatin, a fusigenic secreted molecule, which is an antagonist to myostatin. Myostatin is expressed by quiescent satellite cells and exerts a negative effect on satellite cell activation <ref name="PMID17996437"/>. IGF-IEa and MGF have also been implicated in satellite cell activation: Hill et al. (2003) demonstrated that these mediators are produced by active muscle in rodents and appear to be positive regulators of muscle hypertrophy<ref name="PMID12892408"><pubmed>12892408</pubmed></ref>. However, whilst MGF is acutely induced and is said to precede satellite cell activation, IGF-IEa has a delayed effect involved in the later phase of regeneration<ref name="PMID12892408"/>. Interestingly, in dystrophic muscles MGF is not produced, suggesting the importance of effective muscle repair to avoid the pathogenesis of muscular dystrophy syndromes <ref name="PMID12892408"/>.

Once activated, the satellite cells migrate out of the basal lamina and enter the cell cycle with coexpression of Pax7 and MyoD <ref name="PMID17996437"/>. This process occurs in conjunction with the Notch signaling pathway<ref name="PMID22493066"><pubmed>22493066</pubmed></ref>. The skeletal myoblasts that are produced divide, express myogenin and downregulate Pax7 then fuse to form myofibres<ref name="PMID17996437"/>.

====The Effects of Motor Nerve Damage on Skeletal Muscle====

''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?''

Chronic spinal cord injury (SCI) affects muscles below the level of the lesion. In terms of fibre type, one review <ref name="PMID19705475"><pubmed>19705475</pubmed></ref>describes the progressive change in fibre type toward faster phenotypes. The fibre phenotype is classified according to its myosin heavy chain (MHC) molecule which is an actin-based motor protein associated with muscle fibre contraction<ref name="PMID19705475"/>. These three MHC isoforms are MHC I, MHC IIa, and MHC IIx <ref name="PMID19705475"/>. In SCI there is a reduction of type I fibres (slow) and upregulation of type IIA and IIX fibres (fast)<ref name="PMID19705475"/>. The metabolism of the fast fibres is characterised by a predominantly anaerobic metabolism with fewer mitochondria, unlike type I fibres which undergo aerobic metabolism <ref name="PMID19705475"/>. This is in part due to a reduction in absolute activities of the muscle metabolic enzymes in SCI, favouring the fast glycolytic/oxidative type which fatigue more easily <ref name="PMID19705475"/>.

In terms of fibre size, a study by Castro et al. (1998) <ref name="PMID9887150"><pubmed>9887150</pubmed></ref> found that all fibre types underwent significant atrophy and decreased in size from the 6th to 24th week after injury<ref name="PMID9887150"/>. Moreover, average fibre cross-sectional area decreased by 22% by the 6th week post-injury <ref name="PMID9887150"/>. The changes were accompanied by either complete paralysis or loss of force with increased susceptibility to fatigue depending on the extent of injury <ref name="PMID9887150"/>. Note that whilst type II fibre atrophy is seen during the first months after complete SCI, type I fibres undergo atrophy in the later stages <ref name="PMID19705475"><pubmed>19705475</pubmed></ref>.

Interestingly, the level of the motor neuron lesion can affect the outcome of the muscle atrophy: a study by Stilwill and Sagha <ref name="PMID66912"><pubmed>66912</pubmed></ref>found that lower motor neuron lesions led to muscle fibre grouped atrophy and fibre-type grouping, whereas upper motor neuron lesions led to preferential atrophy of type II fibers with fibre-type grouping.

'''References'''
<references/>

===Lab 8 Assessment===
1. Each student should now look at each of the other Group projects in the class.

2. Next prepare a critical assessment (should include both positive and negative issues) of each project using the project assessment criteria.

3. This assessment should be pasted without signature on the top of the specific project's discussion page. (minimum length 3-5 paragraphs/project)

4. This critical assessment should also be pasted on your own student page. Each student should therefore have 5 separate reports pasted on their own page for this assessment item. Length, quality and accuracy of your reports will be part of the overall mark for this assessment (there will be a greater loading on this than simple question assessments).

====Vision====
In regards to the information presented (outcomes 1 and 9), as the project is still in progress it is understandable that some areas are incomplete. There is so far good, concise information on the structure of the development of the eye and the structures involved in vision. It would be useful to include information on the genetic factors involved in vision development as well as have a section explaining the processes involved with vision. Also, for the Current Research section (outcome 5), it would be better to explain the aims and findings of the research papers cited rather than just referencing the papers and images without describing their significance to research progress. In terms of peer teaching (outcome 4), the page contains a good balance between technical terms and simple language for understanding on the development of structures for vision; additionally, the inclusion Glossary helps to clarify any technical terms.

The most striking part of the layout (outcome 2) is the use of images to demonstrate the development of structures involved in vision. This is great because it makes the page interesting and provides a visual understanding on the development of the eye. However, at times the images could be better placed: for example, in the introduction the pictures appear stacked on top of one another. Additionally, the images in the introduction show similar structures, so perhaps select only one to better aid the flow and appearance of the page. Throughout the page, the images utilised could be provided with more description and linked to the text in order to improve flow and enhance written explanation. Perhaps some information, such as the timeline, could be sorted into a table to improve the layout.

In regards to outcome 3, some of the information provided (e.g. in the section on Development) is not referenced. Additionally, some of the references in the Reference list need to be formatted correctly with author, date, title of the page, publisher (if required) and any other necessary information. It would be useful to follow the style of the automatic default referencing.
Hope the feedback helps and all the best with your project!

====Somatosensory====
The introduction is good in that there is a description of the role of somatosensory functions as well as an overview of its development. To improve further, perhaps avoid trailing off in the final sentence and perhaps put something that concludes your introduction.

In regards to the information presented and layout (outcomes 1, 2, 4 and 9), the history of discoveries is very brief and requires more research. Additionally, it would be useful to set up a timeline to add interest. The section on the central somatosensory differentiation appeared very well researched with a very interesting picture to accompany the text – good work. The section on Touch would better be placed in a table and have accompanying images to avoid getting too ‘wordy’. Also, this section does not have any consistent referencing in the bulk of the content – please cite where you find your information. The section on pain is well researched and has a strong content, however, to enhance this section I would suggest using dot points to describe the different fibres and add a relevant image. Similarly, the hot/cold and pressure sections were great in terms of content but could use with some dot points and visual explanation to make the page more interesting. Just a note on pressure – avoid getting repetitive; the page had already defined the Ruffini’s endings/corpuscles etc in the section of Touch. Additionally, the 2 urls at the bottom of this section are distracting, make sure to incorporate these in your reference list of add them to an ‘External Links’ section. Your Current Research section requires some proof reading and additional articles to make it more comprehensive. However, you have referenced the image well and referred to it in the accompanying text.

In terms of referencing, I noticed some areas where the in-text references were not correctly formatted and were in the (Author, date) style. Perhaps have a look at the referencing tutorial on the Embryology ‘Students’ page to get an understanding of the codes required for citations. For peer teaching (outcome 4), make sure that you define all technical terms – your Glossary only has 2 definitions provided. Other than this, the content overall is interesting to read just make sure you are striking a balance between images and text. Hope it helps and all the best!

====Taste====

In regards to the information presented (outcomes 1 and 9), the timeline for the development is good and written with clarity. However, I noticed the section on structure only referred to the adult state rather than focusing on the embryonic origin of each structure (ectoderm, endoderm and mesoderm). I would suggest that you elaborate on the developmental stages introduced in the timeline in order to build on the information you have already provided. This is important in regards to outcome 6 so that you can relate your research to embryology – the development of taste should be your focus. The history timeline was great to read as it was very concise and clear.

The page shows a good level of peer teaching with clear language and a good balance between images and text (outcome 4) with technical terms explained in the glossary. An improvement could be to make a link between any technical language and the glossary to avoid scrolling up and down to the page. Your Current Research section (outcome 5) was very interesting to read and showed you went beyond the scope of basic research on taste – good work!

In terms of layout (outcome 2), whilst the images are interesting and relevant to the text, some are not appropriately referenced nor described; make sure to reference appropriately and at least write one or two sentences to make the images relevant to the reader. Additionally, the introduction should not be under another subheading (Gustatory system) as it creates some confusion; I would suggest making the introduction its own heading in order to make the page flow. Similarly, the history timeline would best be placed towards the beginning of the page, under the introduction.

I noticed some areas (such as the section on Structure) were not appropriately or consistently referenced. Make sure to include a citation anytime you introduce a researched idea or information to avoid being accused of plagiarism. I noticed the history timeline had good consistent referencing; however the numbers just need to be formatted so they come under the reference list. If you click on the Tutorial: References page linked from the student page, it tells you how to do this. Hope the feedback helps and all the best for your project!

====Abnormal Vision====
"The introduction is good in the manner that it provides some brief background information regarding the normal development of the eye and abnormalities. Additionally, I liked how the introduction described the aims of the page because it sets up a structure for the reader to follow. Just make sure to proof read this section: “The development of the eye is very sensitive and REQUIRES accurate...”

In regards to the information presented and layout (outcomes 1, 2, 4 and 9):

1. Normal Eye Development: This section appears very well researched. I like how you referred to the stages throughout development. However, this section could be enhanced by adding an image of the normal eye structure and development – this acts as a reference point for your page viewers, allowing for a clear visual comparison between the abnormalities and normal structure.

2. Abnormal Development: I like the overview provided at the beginning as it sets the scene for what points you will be covering in this section. Great job. All sections are quite good, just perhaps include more images to further enhance your page.

a. Abnormal lens development: I liked how you first described the function of the gene in development and then stated any abnormalities that arise when the gene is not expressed or mutated. I liked how you included an image for the crystalline genes; just make sure to refer to the image in text (e.g. see fig. 1. or see accompanying image).

b. Abnormal corneal development: Similar to the abnormal lens section, there is a good explanation provided for each gene involved. Just some improvements: make sure to reference all information; e.g. No reference provided for “The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of....”. The accompanying image has been referenced correctly and described, good work!

c. Abnormal retinal development: Once again, a great scope of research and information and suitable image. I liked how you described the impact of each mutation explicitly such as in Albinism “ganglion cells of retina decreased by 25%”. This really helps the reader to understand the extent of the abnormalities from certain gene mutations.

3. Ocular manifestations: the opening sentence is slightly vague. Could you please state which two separate sections that you are referring to? The section that follows could be better organised. It seems to jump from genetic issues to a research timeline then to future research on that disease to another example of a genetic mutation which produces abnormalities. I would suggest putting the research timeline shortly after the introduction and integrating research history not just on LCA but other abnormalities as well. However, the content for all these sections is well referenced and interesting to read. The balance between text and images between LCA and anopthalmia/micropthalmia sections is good and are both really interesting to read! I liked how you provided some epidemiological data and clinical manifestations in depth accompanied by suitable images. However, the environmental abnormalities section could use with more dot-point styles and images to enhance the presentation and aid in your descriptions.

In regards to peer teaching (outcome 5), this page was an absolute joy to read and all technical language was explained in the glossary. Just make sure to pay attention to those minor improvements. Good job!"

====Hearing====

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

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

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

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

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

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

===Lab 9 Assessment===

====Embryonic Blood Flow and Oxygen and the Developing Pancreas====

''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.''

A study by Shah et al.<ref name="PMID21050843"><pubmed>21050843</pubmed></ref> sought to investigate whether enhanced blood flow and oxygen in a developing mouse pancreas correlates with changes in differentiation during embryonic pancreatic development. This investigation was prompted because "there is a fundamental lack of understanding of how organs in early mammalian embryos are able to form despite receiving little or no blood flow" according to Shah et al.

The methods involved injecting fluorescein-conjugated tomato lectin (a vascular tracer) into the hearts of developing mouse embryos ''in utero'' at different stages of development, guided by ultrasound backscatter microscopy. The vascular tracer was left to circulate for 10 minutes and then the mice embryos were harvested for analysis of blood flow and oxygenation. One key finding discovered through immunohistochemistry was that the developing pancreas had dense vascularity, though numerous vessels early in gestation were non-perfused. Vessels that were not perfused with blood did not induce differentiation of adjacent pancreatic epithelium. In contrast, vessels perfused with blood were surrounded by glucagon-positive and insulin-positive cells; these are indications of pancreatic cell differentiation. However, ''in vitro'' it was found that the hypoxic embryonic pancreas shows proliferation but not differentiation. Interestingly, the endocrine areas tended to be areas with flow and higher oxygenation compared to the exocrine areas of the pancreas. Moreover, later embryonic stages when global pancreatic perfusion occurred correlated with a rapid increase in exocrine differentiation. Overall, Shah et al. concluded that vascular flow with oxygenated blood, as opposed to just vascular endothelium alone, may provide specific signals for pancreatic differentiation in the early embryo.

====Developing Teeth====
''2. Identify the embryonic layers and tissues that contribute to the developing teeth.
''
Through the interaction between the neural crest and the ectoderm, 10 teeth buds form in the the embryo on in the early embryo<ref>Universities of Fribourg, Lausanne and Bern. (2012). ''Development of the Teeth''. Retrieved from http://www.embryology.ch/anglais/sdigestive/gesicht05.html</ref>. Each tooth bud has an outer area of ectodermal orgign (the enamel organ) with an inner area of dental pulp made up of solidified mesenchyme of neuroectodermal origin. The neuroectodermal mesenchyme also forms the dental follicle from which the periodontium and cement of the tooth root arise.

* '''Ectoderm''' of the oral cavity produces:
** Ameloblasts which produce the teeth enamel in the direction of the tooth pulp.
* Surrounding '''mesoderm''' (mesenchyme) in conjunction with '''neural crest''' produces:
** Odontoblasts excrete predentin below the ameloblast layer; dentin then arises through calcium salt deposition in the predentin.
** Cementoblasts in the root of the tooth produce cement.

References
<references/>

==Lab Attendance==
Lab 1 --[[User:Z3333038|Z3333038]] 11:49, 25 July 2012 (EST)

Lab 2 --[[User:Z3333038|Z3333038]] 10:05, 1 August 2012 (EST)

Lab 3 --[[User:Z3333038|Z3333038]] 10:01, 8 August 2012 (EST)

Lab 4 --[[User:Z3333038|Z3333038]] 10:00, 15 August 2012 (EST)

Lab 5 --[[User:Z3333038|Z3333038]] 09:59, 22 August 2012 (EST)

Lab 6 --[[User:Z3333038|Z3333038]] 10:10, 29 August 2012 (EST)

Lab 7 --[[User:Z3333038|Z3333038]] 10:09, 12 September 2012 (EST)

Lab 8 --[[User:Z3333038|Z3333038]] 10:00, 19 September 2012 (EST)

Lab 9 --[[User:Z3333038|Z3333038]] 10:03, 26 September 2012 (EST)

User:Z3333038

2012-10-02T09:11:41Z

Z3333038: /* Lab 9 Assessment */

==Individual Assessments==

===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 History of In Vitro Fertilisation====
In vitro fertilisation (IVF) refers to the process of artificial fertilisation conducted ex vivo. The IVF technique was first described for non-human use. The earliest known research conducted was by Walter Heape from Cambridge University in the 1890s who reported the first known case of embryo transplantation in rabbits. In 1959, Dr. Min Chueh Chang published his work in Nature describing the first successful mammalian live birth (rabbits) after IVF therapy.

Eventually, the use of IVF for humans became a possibility and then a reality: in 1978, the first successful birth from IVF occurred in England. The success of this IVF birth is credited to Patrick Steptoe and Robert Edwards. In 2010, Edwards was awarded the [http://www.nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html/ Nobel Prize in Medicine] for the development of human IVF therapy. Because of IVF, many couples have been given a chance to conceive. However, the [http://www.ivf-worldwide.com/ivf-history.html/ history of IVF] is still in the making with constant improvements in the technology being developed and applied.

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

====Research in Fertilisation====

In order for fusion between mammalian gametes to occur, a spermatozoon must first pass through the external layers surrounding the oocyte: the cumulus oophorus and the zona pellucida (ZP). It is believe that the acromosome reaction (AR) of the spermatozoa starts upon contact with the zona pellucida. Consequently, the cumulus cell layer is typically removed in studies of mouse sperm-oocyte interactions in order to facilitate fertilisation. The recent experiments of Jin et al. <ref name="PMID21383182"><pubmed>21383182</pubmed></ref> sought to answer the question: "Where does the fertilising mouse spermatozoon begin the AR - in the cumulus [of the oocyte] or the zona pellucida?" Jin et al. <ref name="PMID21383182"/> utilised fluorescence microscopy and transgenic mouse spermatozoa to conduct their investigation. Additionally, Jin et al. <ref name="PMID21383182"/> used cumulus-free oocytes and cumulus-enclosed oocytes to study the role of the cumulus cells in fertilisation.

From the experiment, Jin et al. <ref name="PMID21383182"/> found that most fertilising spermatozoa begin the AR before their first contact with the ZP. The significance of this finding was that the spermatozoa with intact acromosomes at the ZP seldom had the ability to penetrate through <ref name="PMID21383182"/>. In contrast, spermatozoa which had already began the AR could easily penetrate the ZP. In regards to the role of the cumulus cells, it was found that cumulus-enclosed oocytes had a higher incidence of fertilisation compared to cumulus-free oocytes <ref name="PMID21383182"/>. Moreover, cumulus-free oocytes had an increased incidence of in vitro fertilisation when incubated with other cumulus-enclosed cells; this finding suggests that cumulus cells harbour an important role in fertilisation <ref name="PMID21383182"/>. However, it is notable that when cumulus-free oocytes were incubated in a cumulus-conditioned medium, no increase in fertilisation rate was noted<ref name="PMID21383182"/>. Overall, two conclusions were made: firstly, that the AR is required by the spermatozoa prior to meeting the ZP for effective fertilisation<ref name="PMID21383182"/>. Secondly, the cumulus oophorus confers benefit in increasing the chance of fertilisation<ref name="PMID21383182"/>.

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 16:58, 11 September 2012 (EST) Question 1 is answered well and linked to appropriate resources. Question 2 is also quite a complete answer to what I requested. The formatting of your description could have been better organised, while it is correct to cite the paper when referring to the findings, this is a little overboard with 9 times within 2 paragraphs. If you had organised the information differently this could have been reduced to 1-2 citations within the text. Alternatively the findings could have been provided as a bullet or numbered list. '''10/10'''

===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.''
====Patterns of ZPC Deposition in Porcine Oocyte-Cumulus Complexes====
[[File:Patterns_of_ZPC_Deposition_in_Porcine_Oocytes.jpg‎]]

Immunofluorescence Detection for ZPC and Ubiquitin in a Porcine Oocyte <ref name="PMID21383844"><pubmed>21383844</pubmed></ref>

'''References'''
<references/>

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

Trophinin is a membrane protein expressed in chorionic villi trophoblasts and in the maternal endometrium. In the early stages of pregnancy, trophinin is strongly expressed along with tastin and bystin, which form a complex; this complex mediates apical cell adhesion between the trophoblasts and the endometrial epithelial cells<ref name="PMID14633596"><pubmed>14633596</pubmed></ref>. The time frame in which trophinin is expressed on the apical aspect of the endometrial cells coincides with the "implantation window"<ref name="PMID14633596"/>; the period in which successful implantation is possible. Trophonin-trophonin adhesion during implantation occurs via signal transduction with bystin and tastin<ref name="PMID22201876"><pubmed>22201876</pubmed></ref>. As a consequence of trophinin-trophinin adhesion, trophectoderm cells become activated for implantation<ref name="PMID22201876"/>. Moreover, there have been reports that endometrial epithelial cells undergo apoptosis upon blastocyst adhesion; human trophoectoderm cells express the Fas ligand which interacts with Fas expressed on the endometrium<ref name="PMID22201876"/>. However, other studies have shown that trophinin-mediated cell adhesion can induce endometrial cell apoptosis through mechanisms other than the Fas/FasL cascade<ref name="PMID22201876"/>.

In regards to ectopic pregnancies located within the fallopian tube, research has shown that trophinin is strongly expressed by both the embryonic trophoblasts and maternal fallopian tube epithelium, induced by human chorionic gonadotrophin (hCG)<ref name="PMID14633596"/>. These findings highlight the function of trophonin in facilitating implantation in conjunction with its role in the pathogenesis of ectopic pregnancies.

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 17:04, 11 September 2012 (EST) Question 1 image has been correctly uploaded and contains all the requested information in the summary box. Question 2 is a good description of this recent paper on trophinin and Implantation. '''10/10'''

===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.''
====Gestational Age versus Post-Fertilisation Age====

Gestation is the period of time between conception and birth (Kaneshiro, 2011; Vishton, 2011). Gestational age is the developmental age of the conceptus based on the presumed first day of the last normal menstrual period to the current date, measured in weeks (Kaneshiro, 2011; Vishton, 2011). In contrast, post-fertilisation age refers to the age of the conceptus expressed in elapsed time since fertilisation (Vishton, 2011). Gestational age is approximately two weeks greater than post-fertilization age (Kaneshiro, 2011; Vishton, 2011). Gestational age is used in human development because its start date can be determined by asking the mother when was the presumed first day of the last normal menstrual period (Kaneshiro, 2011; Vishton, 2011). In contrast, the moment of fertilization must be inferred (Vishton, 2011).

'''References'''

Kaneshiro, N. K. (2011). ''Gestational age''. Retrieved from http://www.umm.edu/ency/article/002367.htm

Vishton, P. M. (2011). ''Embryo Foetus Development Stages''. Retrieved from http://www.livestrong.com/article/92683-embryo-fetus-development-stages/

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

====Tissues Derived From Somites====

'''1. Bone (Sclerotome)'''

Bone tissue consists of cells separated by an extracellular matrix with organic and inorganic components (Marieb, Wilhem & Mallatt, 2010). The organic components of bone consists of cells, collagen fibres and ground substance. The cells include osteoprogenitor cells which give rise to osteoblasts: the producers of new bone matrix (osteoid). Mature osteoblasts, called osteocytes, are trapped in lacunae where they maintain the mature bone; osteocytes may revert to osteoblasts in the incidence of a fracture. Osteoclasts are multinucleated cells with ruffled plasma membrane borders and are involved in bone resorption. Bone resorption is important for bone remodelling to improve tensile strength as well as remodel the newly deposited woven bone into mature bone after a fracture. There are two types of mature (lamellar) bone: compact bone and spongy bone (Marieb et al., 2010). The compact bone occurs towards the periphery and is arranged in Haversian systems: lamellae concentrically arranged around a central Haversian canal containing blood vessels, nerves and osteocytes (Marieb et al., 2010). The different Haversian systems communicate with each other, the periosteum and endosteum through the Volkmann's canals. In contrast, spongy bone in the mature adult appears towards the centre of the diaphysis and metaphysis and is arranged in bony shelves (trabeculae) (Marieb et al., 2010). The gross porous arrangement of spongy bone is important for housing the bone marrow (Marieb et al., 2010)

'''2. The Skin (Dermotome)'''

a. ''Dermis'': The dermis is made up of two main regions: (1) the superficial papillary layer and (2) the deeper reticular layer (Marieb et al., 2010). The superficial papillary layer makes up 20% of the dermis and is areolar connective tissue consisting of collagen and elastic fibres; it includes the dermal papillae which extend into the overlying epidermis to strengthen the dermal-epidermal junction and increase surface area for nutrient, gas and waste exchange with the avascular epidermis (Marieb et al., 2010). The reticular layer is composed of dense irregular connective tissue with thick bundles of collagen and elastic fibres arranged in different planes (Marieb et al., 2010). Other cells interspersed among the connective tissue of the dermis include fibroblasts, macrophages, mast cells and other white blood cells including lymphocytes(Marieb et al., 2010). The dermis is highly vascular and supplied with nerve fibres (Marieb et al., 2010). There are two vascular plexuses; the deep dermal plexus and the subpapillary plexus (Marieb et al., 2010). These vessels serve not only for nutrient supply to the dermis and epidermis, but for temperature regulation as well (Marieb et al., 2010).

b. ''Hypodermis'': The subcutaneous layer, or fatty hypodermis, consists of areolar and adipose connective tissue(Marieb et al., 2010). The cellular components include adipocytes as well as white blood cells (Marieb et al., 2010). The hypodermis serves to store fat and anchor the skin to underlying structure in a manner that the skin can slide over structures(Marieb et al., 2010). Additionally, the adipose in the hypodermis serves an insulator.

'''3. Skeletal Muscle (Myotome)'''
Skeletal muscle fibres come together to form a larger skeletal muscle surrounded by different levels of connective tissue "coats": the epimysium surrounds the whole skeletal muscle, the perimysium covers each fascicle and the loose CT endomysium separates each skeletal muscle fibre (Marieb et al., 2010). The skeletal muscle fibres are long cylindrical cells with a diameter between 10-100um (Marieb et al., 2010) . These muscle fbres are formed by the fusion of embryonic cells and hence contain many nuclei which are located at the periphery of each fibre beneath the sarcolemma, the skeletal muscle cell membrane (Marieb et al., 2010). These muscle fibres appear striated because of the internal organelles of the muscle fibres: myofibrils, the contractile organelles of muscle tissue (Marieb et al., 2010).

'''References'''

Marieb, E. N., Wilhelm, P. B., Mallatt, J. (2010). ''Human Anatomy'' (6th ed.). San Francisco, CA: Pearson Education, Inc.

--[[User:Z8600021|Mark Hill]] 17:10, 11 September 2012 (EST) Question 1 Clearly identified and cited the difference between "gestational age" and "post-fertilisation age". Question 2 you have also identified histological descriptions at least 3 different types of tissues formed from somites. For both questions you could have formatted the references and the reference list by using the <nowiki><ref></ref></nowiki> tags and simply inserted any text that you wanted in your list between the tags. '''10/10'''

===Lab 4 Assessment===

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

*'''Amniocentesis''' <ref>Moore, K. L., Persaud, T. V. N. & Torchia, M. G. (2013). ''The Developing Human'' (9th ed.). Philadelphia, PA: Elsevier Saunders. </ref>: Amniocentesis refers to sampling of the amniotic fluid by inserting a needle through the mother's anterior abdominal and uterine walls into the amniotic cavity by piercing the chorion and amnion. This technique is performed at 15 and 18 weeks gestation. Amniocentesis is often used to detect genetic disorders as it allows for chromosome analysis. One abnormality which can be detected is trisomy 21 (Down's Syndrome)[1]. Additionally, amniocentesis can be utilised for alpha-fetoprotein assays to detect neural tube defects like spina bifida [1].

*'''Chorionic Villus Sampling''' [1]: Biopsies of trophoblastic tissue are obtained by inserting a needle through the mother's abdominal wall and uterine walls to the uterine cavity. Sampling can also be performed through the cervix with a polyethylene catheter, guided by real-time ultrasonography. CVS can be performed sooner than amniocentesis at 10 and 12 weeks of gestation. However, the rate of miscarriage from CVS is higher than amniocentesis. Like amniocentesis, CVS can be used to detect chromosomal abnormalities like trisomy 21 as well as trisomy 18. Additionally, Tay-Sachs disease can be detected with CVS [1].

====The Therapeutic Use of Cord Stem Cells====
''2. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.''

Fu et al. (2006) sought to isolate human umbilical cord mesenchymal stem cells (HUCMSCs) and transform them into dopaminergic neurons in vitro <ref name="PMID16099997"><pubmed>16099997</pubmed></ref>. The experiment was carried out in the interest of finding a potential cure for Parkinson's disease from HUCMSCs [2]. The procedure involved isolating human mesenchymal stem cells from Wharton's jelly of the umbilical cord and culturing the HUCMSCs in a neuronal conditioned medium (NCM) [2]. The differentiation of the HUCMSCs into dopaminergic neurons was induced through stepwise culturing with the NCM, sonic hedgehog and FGF-8 [2]. The successfully transformed HUCMSCs into dopaminergic neurons were selected by positive immunohistochemistry staining for tyrosine hydroxylase (TH), the rate-limiting catecholaminergic synthesizing enzyme, and dopamine secretion [2]. These neurons were then transplanted into the striatum of rats with induced Parkinson's disease by unilateral striatal lesioning with neurotoxin (6-hydroxydopamine hydrogen chloride)[2]. The effects of stem cell transplantation were examined in the Parkinsonian animals by quantification of rotations in the mice in response to amphetamine at 0, 1, 2, 3 and 4 months [2].

Despite a success rate of 12.7% of transformed HUCMSCs, the study found that the original number of HUCMSCs doubled after 3 days of culture [2]. Additionally, the transformed HUCMSCs were still viable in the rats 4 months post-transplantation without the need for immunosuppression [2]. These findings highlight HUCMSCs as a potentially safe source of organs due to their viability post-surgery and the lack of a negative host response to the newly transplanted tissues. Additionally, positive TH staining showed migration of the transformed HUCMSCs rostrally and caudally from the location of implantation [2]. Hence, the transformed HUMSCs were able to integrate properly into the patient (Parkinsonian mouse), putting forth their suitability as a tissue source for transplantation.

The clinical effects of the HUCMSCs on the Parkinsonian mice were assessed by comparing test subjects to two control groups. The first control group consisted of normal, non-Parkinsonian mice with a low score of rotation in response to amphetamine. The second control group contained Parkinsonian mice which received no treatment and had a high rotation score [2]. It was found that the second control group showed no improvement in rotation score and deteriorated further over time. Similarly, mice treated with non-transformed HUCMSCs did not have observable improvements and had a similar deteriorating rotation score to the untreated Parkinsonian animals [2]. This finding highlights that untransformed HUCMSCs confer no clinical benefit in the setting of simulated Parkinson's disease [2]. The Parkinsonian mice treated with transformed HUCMSCs at first had no observable improvement but over time showed significantly improved rotational scores relative to the Parkinsonian control group [2]. However, the transformed HUCMSCs group did not show improvement to the extent of returning to a normal level (non-Parkinsonian rat). These findings suggest that HUCMSCs could be a potential stem cell source for transplantation, however, the procedures for HUMSCs transformation and transplantation must first be reviewed [2]. Fu et al. (2006) suggested that, the number of dopaminergic neurons of implanted cells may have been relatively inadequate to alleviate the Parkinsonism symptoms in the affected rats. Additionally, the transplanted cells may take time to integrate into the host brain: only two rats in the transformed HUCMSCs group survived for at least 8 months, with amphetamine-induced rotation behavior remaining similar to that 4 months after transplantation. Hence, in order to properly assess HUCMSCs to treat Parkinson's disease, the long-term effects of transplantation must be studied [2].

'''References'''
<references/>

--[[User:Z8600021|Mark Hill]] 17:18, 11 September 2012 (EST) Question 1 well answered in terms of technique and specific abnormalities. Question 2 human umbilical cord mesenchymal stem cells in Wharton's jelly have been used in several studies as potential sources of therapeutic cells. Perhaps a more recent paper next time. '''10/10'''

===Lab 7 Assessment===

====Muscle Satellite Cells====

''1. (a) Provide a one sentence definition of a muscle satellite cell''

Satellite cells are quiescent cells located beneath the basal lamina of each myofibre and function as myogenic precursors (stem cells) for postnatal muscle growth and repair <ref name="PMID16051152"><pubmed>16051152</pubmed></ref>.

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

Muscle satellite cells are at rest (G0) when skeletal muscle is not active<ref name="PMID22649641"><pubmed>22649641</pubmed></ref>. Activation can occur in the settings of physical activity and mechanical trauma <ref name="PMID12892408"/>. When satellite cells are activated, they proliferate and are converted to myoblasts which further differentiate and fuse with existing muscle fibres or form new fibres <ref name="PMID12892408"><pubmed>12892408</pubmed></ref>. The myonuclei accumulated in the tissue are of key importance for myogenesis: they aid in increasing protein synthesis and enable muscle growth (hypertrophy and hyperplasia) and regeneration<ref name="PMID16051152"/>. Without satellite cells, mature muscle fibres are unable to undergo regeneration <ref name="PMID16051152"/>. There is much speculation as to the exact mechanisms and factors which activate muscle satellite cells. It is proposed that strenuous exercise, mechanical muscle injury or myodegenerative disease result in the inflammatory response which recruits neutrophils and macrophages to the area of damage; the inflammatory mediators released in conjunction with growth factors secreted by the myofibres promote myosatellite activation <ref name="PMID12892408"/>. One proposed "triggering agent" is the production of sphingosine-1-phosphate from the inner part of the plasma membrane leading to satellite cell entry into the cell cycle <ref name="PMID17996437"><pubmed>17996437</pubmed></ref>. Additionally, mechanical stretch to the muscle fibre has been shown to trigger intracellular signals, such as nitric oxide synthesis which results in hepatocyte growth factor (HGF) release <ref name="PMID17996437"/>. Nitric oxide also induces follistatin, a fusigenic secreted molecule, which is an antagonist to myostatin. Myostatin is expressed by quiescent satellite cells and exerts a negative effect on satellite cell activation <ref name="PMID17996437"/>. IGF-IEa and MGF have also been implicated in satellite cell activation: Hill et al. (2003) demonstrated that these mediators are produced by active muscle in rodents and appear to be positive regulators of muscle hypertrophy<ref name="PMID12892408"><pubmed>12892408</pubmed></ref>. However, whilst MGF is acutely induced and is said to precede satellite cell activation, IGF-IEa has a delayed effect involved in the later phase of regeneration<ref name="PMID12892408"/>. Interestingly, in dystrophic muscles MGF is not produced, suggesting the importance of effective muscle repair to avoid the pathogenesis of muscular dystrophy syndromes <ref name="PMID12892408"/>.

Once activated, the satellite cells migrate out of the basal lamina and enter the cell cycle with coexpression of Pax7 and MyoD <ref name="PMID17996437"/>. This process occurs in conjunction with the Notch signaling pathway<ref name="PMID22493066"><pubmed>22493066</pubmed></ref>. The skeletal myoblasts that are produced divide, express myogenin and downregulate Pax7 then fuse to form myofibres<ref name="PMID17996437"/>.

====The Effects of Motor Nerve Damage on Skeletal Muscle====

''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?''

Chronic spinal cord injury (SCI) affects muscles below the level of the lesion. In terms of fibre type, one review <ref name="PMID19705475"><pubmed>19705475</pubmed></ref>describes the progressive change in fibre type toward faster phenotypes. The fibre phenotype is classified according to its myosin heavy chain (MHC) molecule which is an actin-based motor protein associated with muscle fibre contraction<ref name="PMID19705475"/>. These three MHC isoforms are MHC I, MHC IIa, and MHC IIx <ref name="PMID19705475"/>. In SCI there is a reduction of type I fibres (slow) and upregulation of type IIA and IIX fibres (fast)<ref name="PMID19705475"/>. The metabolism of the fast fibres is characterised by a predominantly anaerobic metabolism with fewer mitochondria, unlike type I fibres which undergo aerobic metabolism <ref name="PMID19705475"/>. This is in part due to a reduction in absolute activities of the muscle metabolic enzymes in SCI, favouring the fast glycolytic/oxidative type which fatigue more easily <ref name="PMID19705475"/>.

In terms of fibre size, a study by Castro et al. (1998) <ref name="PMID9887150"><pubmed>9887150</pubmed></ref> found that all fibre types underwent significant atrophy and decreased in size from the 6th to 24th week after injury<ref name="PMID9887150"/>. Moreover, average fibre cross-sectional area decreased by 22% by the 6th week post-injury <ref name="PMID9887150"/>. The changes were accompanied by either complete paralysis or loss of force with increased susceptibility to fatigue depending on the extent of injury <ref name="PMID9887150"/>. Note that whilst type II fibre atrophy is seen during the first months after complete SCI, type I fibres undergo atrophy in the later stages <ref name="PMID19705475"><pubmed>19705475</pubmed></ref>.

Interestingly, the level of the motor neuron lesion can affect the outcome of the muscle atrophy: a study by Stilwill and Sagha <ref name="PMID66912"><pubmed>66912</pubmed></ref>found that lower motor neuron lesions led to muscle fibre grouped atrophy and fibre-type grouping, whereas upper motor neuron lesions led to preferential atrophy of type II fibers with fibre-type grouping.

'''References'''
<references/>

===Lab 8 Assessment===
1. Each student should now look at each of the other Group projects in the class.

2. Next prepare a critical assessment (should include both positive and negative issues) of each project using the project assessment criteria.

3. This assessment should be pasted without signature on the top of the specific project's discussion page. (minimum length 3-5 paragraphs/project)

4. This critical assessment should also be pasted on your own student page. Each student should therefore have 5 separate reports pasted on their own page for this assessment item. Length, quality and accuracy of your reports will be part of the overall mark for this assessment (there will be a greater loading on this than simple question assessments).

====Vision====
In regards to the information presented (outcomes 1 and 9), as the project is still in progress it is understandable that some areas are incomplete. There is so far good, concise information on the structure of the development of the eye and the structures involved in vision. It would be useful to include information on the genetic factors involved in vision development as well as have a section explaining the processes involved with vision. Also, for the Current Research section (outcome 5), it would be better to explain the aims and findings of the research papers cited rather than just referencing the papers and images without describing their significance to research progress. In terms of peer teaching (outcome 4), the page contains a good balance between technical terms and simple language for understanding on the development of structures for vision; additionally, the inclusion Glossary helps to clarify any technical terms.

The most striking part of the layout (outcome 2) is the use of images to demonstrate the development of structures involved in vision. This is great because it makes the page interesting and provides a visual understanding on the development of the eye. However, at times the images could be better placed: for example, in the introduction the pictures appear stacked on top of one another. Additionally, the images in the introduction show similar structures, so perhaps select only one to better aid the flow and appearance of the page. Throughout the page, the images utilised could be provided with more description and linked to the text in order to improve flow and enhance written explanation. Perhaps some information, such as the timeline, could be sorted into a table to improve the layout.

In regards to outcome 3, some of the information provided (e.g. in the section on Development) is not referenced. Additionally, some of the references in the Reference list need to be formatted correctly with author, date, title of the page, publisher (if required) and any other necessary information. It would be useful to follow the style of the automatic default referencing.
Hope the feedback helps and all the best with your project!

====Somatosensory====
The introduction is good in that there is a description of the role of somatosensory functions as well as an overview of its development. To improve further, perhaps avoid trailing off in the final sentence and perhaps put something that concludes your introduction.

In regards to the information presented and layout (outcomes 1, 2, 4 and 9), the history of discoveries is very brief and requires more research. Additionally, it would be useful to set up a timeline to add interest. The section on the central somatosensory differentiation appeared very well researched with a very interesting picture to accompany the text – good work. The section on Touch would better be placed in a table and have accompanying images to avoid getting too ‘wordy’. Also, this section does not have any consistent referencing in the bulk of the content – please cite where you find your information. The section on pain is well researched and has a strong content, however, to enhance this section I would suggest using dot points to describe the different fibres and add a relevant image. Similarly, the hot/cold and pressure sections were great in terms of content but could use with some dot points and visual explanation to make the page more interesting. Just a note on pressure – avoid getting repetitive; the page had already defined the Ruffini’s endings/corpuscles etc in the section of Touch. Additionally, the 2 urls at the bottom of this section are distracting, make sure to incorporate these in your reference list of add them to an ‘External Links’ section. Your Current Research section requires some proof reading and additional articles to make it more comprehensive. However, you have referenced the image well and referred to it in the accompanying text.

In terms of referencing, I noticed some areas where the in-text references were not correctly formatted and were in the (Author, date) style. Perhaps have a look at the referencing tutorial on the Embryology ‘Students’ page to get an understanding of the codes required for citations. For peer teaching (outcome 4), make sure that you define all technical terms – your Glossary only has 2 definitions provided. Other than this, the content overall is interesting to read just make sure you are striking a balance between images and text. Hope it helps and all the best!

====Taste====

In regards to the information presented (outcomes 1 and 9), the timeline for the development is good and written with clarity. However, I noticed the section on structure only referred to the adult state rather than focusing on the embryonic origin of each structure (ectoderm, endoderm and mesoderm). I would suggest that you elaborate on the developmental stages introduced in the timeline in order to build on the information you have already provided. This is important in regards to outcome 6 so that you can relate your research to embryology – the development of taste should be your focus. The history timeline was great to read as it was very concise and clear.

The page shows a good level of peer teaching with clear language and a good balance between images and text (outcome 4) with technical terms explained in the glossary. An improvement could be to make a link between any technical language and the glossary to avoid scrolling up and down to the page. Your Current Research section (outcome 5) was very interesting to read and showed you went beyond the scope of basic research on taste – good work!

In terms of layout (outcome 2), whilst the images are interesting and relevant to the text, some are not appropriately referenced nor described; make sure to reference appropriately and at least write one or two sentences to make the images relevant to the reader. Additionally, the introduction should not be under another subheading (Gustatory system) as it creates some confusion; I would suggest making the introduction its own heading in order to make the page flow. Similarly, the history timeline would best be placed towards the beginning of the page, under the introduction.

I noticed some areas (such as the section on Structure) were not appropriately or consistently referenced. Make sure to include a citation anytime you introduce a researched idea or information to avoid being accused of plagiarism. I noticed the history timeline had good consistent referencing; however the numbers just need to be formatted so they come under the reference list. If you click on the Tutorial: References page linked from the student page, it tells you how to do this. Hope the feedback helps and all the best for your project!

====Abnormal Vision====
"The introduction is good in the manner that it provides some brief background information regarding the normal development of the eye and abnormalities. Additionally, I liked how the introduction described the aims of the page because it sets up a structure for the reader to follow. Just make sure to proof read this section: “The development of the eye is very sensitive and REQUIRES accurate...”

In regards to the information presented and layout (outcomes 1, 2, 4 and 9):

1. Normal Eye Development: This section appears very well researched. I like how you referred to the stages throughout development. However, this section could be enhanced by adding an image of the normal eye structure and development – this acts as a reference point for your page viewers, allowing for a clear visual comparison between the abnormalities and normal structure.

2. Abnormal Development: I like the overview provided at the beginning as it sets the scene for what points you will be covering in this section. Great job. All sections are quite good, just perhaps include more images to further enhance your page.

a. Abnormal lens development: I liked how you first described the function of the gene in development and then stated any abnormalities that arise when the gene is not expressed or mutated. I liked how you included an image for the crystalline genes; just make sure to refer to the image in text (e.g. see fig. 1. or see accompanying image).

b. Abnormal corneal development: Similar to the abnormal lens section, there is a good explanation provided for each gene involved. Just some improvements: make sure to reference all information; e.g. No reference provided for “The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of....”. The accompanying image has been referenced correctly and described, good work!

c. Abnormal retinal development: Once again, a great scope of research and information and suitable image. I liked how you described the impact of each mutation explicitly such as in Albinism “ganglion cells of retina decreased by 25%”. This really helps the reader to understand the extent of the abnormalities from certain gene mutations.

3. Ocular manifestations: the opening sentence is slightly vague. Could you please state which two separate sections that you are referring to? The section that follows could be better organised. It seems to jump from genetic issues to a research timeline then to future research on that disease to another example of a genetic mutation which produces abnormalities. I would suggest putting the research timeline shortly after the introduction and integrating research history not just on LCA but other abnormalities as well. However, the content for all these sections is well referenced and interesting to read. The balance between text and images between LCA and anopthalmia/micropthalmia sections is good and are both really interesting to read! I liked how you provided some epidemiological data and clinical manifestations in depth accompanied by suitable images. However, the environmental abnormalities section could use with more dot-point styles and images to enhance the presentation and aid in your descriptions.

In regards to peer teaching (outcome 5), this page was an absolute joy to read and all technical language was explained in the glossary. Just make sure to pay attention to those minor improvements. Good job!"

====Hearing====

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

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

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

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

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

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

===Lab 9 Assessment===

====Embryonic Blood Flow and Oxygen and the Developing Pancreas====

''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.''

A study by Shah et al.<ref name="PMID21050843"><pubmed>21050843</pubmed></ref> sought to investigate whether enhanced blood flow and oxygen in a developing mouse pancreas correlates with changes in differentiation during embryonic pancreatic development. This investigation was prompted because "there is a fundamental lack of understanding of how organs in early mammalian embryos are able to form despite receiving little or no blood flow" according to Shah et al.

The methods involved injecting fluorescein-conjugated tomato lectin (a vascular tracer) into the hearts of developing mouse embryos ''in utero'' at different stages of development, guided by ultrasound backscatter microscopy. The vascular tracer was left to circulate for 10 minutes and then the mice embryos were harvested for analysis of blood flow and oxygenation. One key finding discovered through immunohistochemistry was that the developing pancreas had dense vascularity, though numerous vessels early in gestation were non-perfused. Vessels that were not perfused with blood did not induce differentiation of adjacent pancreatic epithelium. In contrast, vessels perfused with blood were surrounded by glucagon-positive and insulin-positive cells; these are indications of pancreatic cell differentiation. However, ''in vitro'' it was found that the hypoxic embryonic pancreas shows proliferation but not differentiation. Interestingly, the endocrine areas tended to be areas with flow and higher oxygenation compared to the exocrine areas of the pancreas. Moreover, later embryonic stages when global pancreatic perfusion occurred correlated with a rapid increase in exocrine differentiation. Overall, Shah et al. concluded that vascular flow with oxygenated blood, as opposed to just vascular endothelium alone, may provide specific signals for pancreatic differentiation in the early embryo.

====Developing Teeth====
2. Identify the embryonic layers and tissues that contribute to the developing teeth.

Through the interaction between the neural crest and the ectoderm, 10 teeth buds form in the the embryo on in the early embryo<ref>Universities of Fribourg, Lausanne and Bern. (2012). ''Development of the Teeth''. Retrieved from http://www.embryology.ch/anglais/sdigestive/gesicht05.html</ref>. Each tooth bud has an outer area of ectodermal orgign (the enamel organ) with an inner area of dental pulp made up of solidified mesenchyme of neuroectodermal origin. The neuroectodermal mesenchyme also forms the dental follicle from which the periodontium and cement of the tooth root arise.

* '''Ectoderm''' of the oral cavity
** Ameloblasts which produce the teeth enamel in the direction of the
* Surrounding '''mesoderm''' (mesenchyme) in conjunction with '''neural crest''' i.e. neural crest derived mesenchyme:
** Odontoblasts excrete predentin below the ameloblast layer; dentin then arises through calcium salt deposition in the predentin.
** Cementoblasts in the root of the tooth produce cement.

References
<references/>

==Lab Attendance==
Lab 1 --[[User:Z3333038|Z3333038]] 11:49, 25 July 2012 (EST)

Lab 2 --[[User:Z3333038|Z3333038]] 10:05, 1 August 2012 (EST)

Lab 3 --[[User:Z3333038|Z3333038]] 10:01, 8 August 2012 (EST)

Lab 4 --[[User:Z3333038|Z3333038]] 10:00, 15 August 2012 (EST)

Lab 5 --[[User:Z3333038|Z3333038]] 09:59, 22 August 2012 (EST)

Lab 6 --[[User:Z3333038|Z3333038]] 10:10, 29 August 2012 (EST)

Lab 7 --[[User:Z3333038|Z3333038]] 10:09, 12 September 2012 (EST)

Lab 8 --[[User:Z3333038|Z3333038]] 10:00, 19 September 2012 (EST)

Lab 9 --[[User:Z3333038|Z3333038]] 10:03, 26 September 2012 (EST)

Talk:2012 Group Project 4

2012-10-02T00:44:32Z

Z3333038: /* Signal Transduction */

{{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.

------

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.

----

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 ☺

----

- 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.

----------

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.

Talk:2012 Group Project 4

2012-10-02T00:40:01Z

Z3333038: /* 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)

==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.

----------

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)

----

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.

----

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!
--------

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 :)

----

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.

----

* '''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.

----

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.

----
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)

----

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.

2012 Group Project 4

2012-10-02T00:36:01Z

Z3333038: /* Clinical Features */

[[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===

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.

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. 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.

[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]

{{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

2012-10-02T00:30:33Z

Z3333038: /* Clinical Features */

[[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"/>.

====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|330px|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]

{{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

2012-10-02T00:29:43Z

Z3333038: /* Congenital Abnormalities */

[[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"/>.

====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|350px|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]

{{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

2012-10-02T00:27:03Z

Z3333038: /* Clinical Features */

[[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"/>.

====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|350px|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]

{{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

2012-10-02T00:25:57Z

Z3333038: /* Kallmann's Syndrome */

[[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"/>.

====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|250px|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]

{{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

2012-10-02T00:25:05Z

Z3333038: /* Congenital Abnormalities */

[[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"/>.

====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|250px|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====
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====
[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|500px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]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]

{{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

2012-10-02T00:22:27Z

Z3333038: /* Congenital Abnormalities */

[[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"/>.

====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|250px|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====
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====
[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|500px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]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]

{{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

2012-10-02T00:20:56Z

Z3333038: /* Clinical Features */

[[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"/>.

====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|350px|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====
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====
[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]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]

{{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

2012-10-02T00:09:05Z

Z3333038: /* Clinical Features */

[[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"/>.

====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|350px|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 type of obstruction (unilateral or bilateral) and the presence of other craniofacial abnormalities<ref name="PMID19328897"/>.

'''Bilateral'''
* At birth present with ''asphyxia neonatorum'': pathological changes caused by hypoxia from affected respiration. A medical emergency requiring intubation then immediate surgical intervention<ref name="PMID19328897"/>.
* Obvious airway obstruction <ref name="PMID19328897"/>
* Stridor, a harsh vibrating sound when breathing <ref name="PMID19328897"/>
* Paradoxical cyanosis

Unilateral

===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====
[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]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]

{{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

2012-10-02T00:08:06Z

Z3333038: /* Clinical Features */

[[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"/>.

====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|350px|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 type of obstruction (unilateral or bilateral) and the presence of other craniofacial abnormalities<ref name="PMID19328897"/>.

'''Bilateral'''
* At birth present with ''asphyxia neonatorum'': pathological changes caused by hypoxia from affected respiration. A medical emergency requiring intubation then immediate surgical intervention<ref name="PMID19328897"/>.
* Obvious airway obstruction <ref name="PMID19328897"/>
* Stridor, a harsh vibrating sound when breathing <ref name="PMID19328897"/>
* Paradoxical cyanosis

Unilateral

===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====
[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]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]

{{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}}

Talk:2012 Group Project 4

2012-10-01T23:54:10Z

Z3333038: /* 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)

==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.

-------

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.

------

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.

----------

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)

----

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!
--------

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.

----

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?

2012 Group Project 4

2012-10-01T09:04:12Z

Z3333038: /* Clinical Features */

[[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"/>.

====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|350px|thumb|right|Computed Tomography of Choanal Atresia]] The severity of the clinical features of choanal atresia depends on the type of obstruction (unilateral or bilateral) and the presence of other craniofacial abnormalities<ref name="PMID19328897"/>.

Unilateral

Bilateral

===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====
[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]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]

{{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

2012-10-01T08:44:20Z

Z3333038: /* 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|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"/>.

====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|350px|thumb|right|Computed Tomography of Choanal Atresia]] The severity of the clinical features of choanal atresia depends on the type of obstruction (unilateral or bilateral) and the presence of other craniofacial abnormalities<ref name="PMID19328897"/>.

===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====
[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]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]

{{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

2012-10-01T08:40:15Z

Z3333038: /* 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|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"/>.

====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|350px|thumb|right|Computed Tomography of Choanal Atresia]]

===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====
[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]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]

{{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

2012-10-01T08:33:34Z

Z3333038: /* 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|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"/>.

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate.

<table>
{| width=100%
|-bgcolor="FF9900 "
| width=20%|'''Risk Factor Model'''
| width=80%|'''Description'''
|-bgcolor="FFFF99"
| ''' Embryonic Models'''
| 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 Factors'''
|
* 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 Models'''
|
* '''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'''
|}
</table>

====Clinical Features====

[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

===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====
[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]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]

{{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

2012-10-01T08:12:21Z

Z3333038: /* 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|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"/>.

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate.

<table>
{| width=100%
|-bgcolor="FF9900 "
| width=20%|'''Risk Factor Model'''
| width=80%|'''Description'''
|-bgcolor="FFFF99"
| ''' Embryonic Models'''
| 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 Factors'''
|
* 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 Models'''
|
* '''Thionamides'''
* '''Retinoic Acid'''
|}
</table>

====Clinical Features====

[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

===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====
[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]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]

{{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

2012-10-01T08:10:01Z

Z3333038: /* 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|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"/>.

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate.

<table>
{| width=100%
|-bgcolor="FF9900 "
| width=20%|'''Risk Factor Model'''
| width=80%|'''Description'''
|-bgcolor="FFFF99"
| ''' Embryonic Models'''
| 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 Factors'''
|* 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 Models'''
| * Retinoic Acid
*
|}
</table>

====Clinical Features====

[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

===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====
[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]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]

{{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

2012-10-01T08:08:43Z

Z3333038: /* 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|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"/>.

====Pathophysiology====
At present, the exact cause of choanal atresia is still under debate.

<table>
{| width=100%
|-bgcolor="FF9900 "
| width=20%|'''Risk Factor Model'''
| width=80%|'''Description'''
|-bgcolor="FFFF99"
| ''' Embryonic Models'''
| 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 Factors
|*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 Models
| * Retinoic Acid
|}
</table>

====Clinical Features====

[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]

===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====
[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]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]

{{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

2012-10-01T08:07:06Z

Z3333038: /* 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|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"/>.

====Pathophysiology====
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]At present, the exact cause of choanal atresia is still under debate.

<table>
{| width=100%
|-bgcolor="FF9900 "
| width=20%|'''Risk Factor Model'''
| width=80%|'''Description'''
|-bgcolor="FFFF99"
'''| Embryonic Models'''
| 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 Factors
|*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 Models
| * Retinoic Acid
|}
</table>

===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====
[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]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]

{{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

2012-10-01T08:05:26Z

Z3333038: /* Congenital Abnormalities */

[[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"/>.

====Pathophysiology====
[[File:Choanal atresia computed tomography 01.jpg|350px|thumb|right|Computed Tomography of Choanal Atresia]]At present, the exact cause of choanal atresia is still under debate.

<table>
{| width=100%
|-bgcolor="FF9900 "
| width=20%|'''Risk Factor Model'''
| width=80%|'''Description'''
|-bgcolor="FFFF99"
| Embryonic Models
| 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 Factors
|*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 Models
| * Retinoic Acid
|}
</table>

===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====
[[File:Normal Neuronal Migration into the Olfactory Bulb Compared to Kallmann's Syndrome.jpg|600px|thumb|right|Olfactory Neuronal Migration in Kallmann's Syndrome]]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]

{{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}}